JP2018150368A - Pharmaceutical compositions comprising dextromethorphan and quinidine for treatment of neurological disorders - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide pharmaceutical compositions for treating neurological disorders, and methods for treating neurological disorders by administering the pharmaceutical compositions.SOLUTION: The compositions comprise dextromethorphan in combination with quinidine.SELECTED DRAWING: Figure 1

Description

  Pharmaceutical compositions and methods for treating neurological diseases are provided. The composition includes dextromethorphan in combination with quinidine.

  Patients with neurodegenerative diseases or brain damage, such as those caused by stroke or head trauma, often suffer from emotional problems associated with the disease or injury. The terms “emotional instability” and “pseudobulbar affect” refer to patients with brain injury such as head trauma, stroke, brain tumor, encephalitis, or amyotrophic lateral sclerosis (ALS, motor neuron disease or (Also called Luguerig disease), a series of symptoms often seen in patients with progressive neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Psychiatrists and neurologists Is used. In the majority of these cases, emotional instability occurs in patients with bilateral injuries involving the subcortical forebrain structures (damages affecting both brain hemispheres).

  Emotional instability is different from the clinical form of reactive or intrinsic depression, and it is an intermittent, paroxysmal emotional eruption that usually occurs at any time or when there is nothing particularly stimulating (usually Is characterized by crying or laughing that is intense or even explosive). Emotional instability or pseudobulbar emotion, by its term, also refers to excessive emotion, emotional incontinence, emotional control, excessive sensitivity, and morbid crying. The patient is well aware that the eruption of emotion is not appropriate in that particular situation, but because the emotional expression cannot be controlled, the sensation associated with emotional instability is often described in words such as “disruption”. The

  Emotional instability or pseudobulbar emotions become a clinical problem when the inability to control the eruption of emotions impedes the ability to engage in housework, private affairs, or work in a substantial way. For example, a businessman with early ALS or Parkinson's disease may not be seated during a business meeting, or one patient may not cry or laugh at an inappropriate time in front of others However, it may be impossible to go out to the public, such as a restaurant or a movie theater, because things are temporarily impossible. These symptoms can occur even if the patient still has enough energy and stamina to do the physical work necessary to interact with others. These emotional eruptions exacerbate other symptoms of the disease in addition to the patient's usual discomfort, inappropriate emotions, confounded emotions, and the visual impact the patient has on others. It might be. These create a sense of exclusion, alienation, and isolation, and it can be very difficult for friends and family to support the patient's tolerance and compassion.

  There remains a need for additional or improved forms of treatment for other chronic diseases such as emotional instability and chronic pain. Such treatment preferably results in at least some improvement in other patients compared to other known drugs. A method of treating emotional instability in a patient suffering from at least some neurological disorder such as progressive neurological disease is desirable.

  In human patients in need of such treatment, suffer from emotional instability, pseudobulbaric emotions, and other chronic illnesses without being too sedated or otherwise significantly disturbing consciousness or agility. A method of treatment is provided. This treatment involves administering dextromethorphan in combination with a minimal dosage of quinidine.

  In a first embodiment, a method of treating pseudobulbar affect or emotional instability comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, the amount of dextromethorphan administered Is from about 20 mg / day to about 200 mg / day and the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.

  In one aspect of the first embodiment, the pseudobulbaric emotion or emotional instability is caused by a neurodegenerative disease or neurodegenerative disease, or brain injury.

  In a second embodiment, a method of treating neuropathic pain comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is about 20 mg / day. A method is provided wherein the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.

  In a third embodiment, a neurodegenerative disease or method of treating neurodegenerative disease comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is about Methods are provided that are 20 mg / day to about 200 mg / day and the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.

  In one aspect of the third embodiment, the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

  In a fourth embodiment, a method of treating brain injury comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is about 20 mg / day to about A method is provided that is 200 mg / day and the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.

  In one aspect of the fourth embodiment, the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event (ischemic event), hypoxic event, and neuronal cell death.

  In certain aspects of the first to fourth embodiments, dextromethorphan and quinidine are administered as a combined drug once per day.

  In certain aspects of the first to fourth embodiments, dextromethorphan and quinidine are administered as a combined drug at least twice per day.

  In certain aspects of the first to fourth embodiments, the amount of quinidine administered is from about 20 mg / day to about 45 mg / day.

  In certain aspects of the first to fourth embodiments, the amount of dextromethorphan administered is from about 20 mg / day to about 60 mg / day.

  In one aspect of the first to fourth embodiments, at least one of quinidine and dextromethorphan is in the form of a pharmaceutically acceptable salt.

  In certain aspects of the first to fourth embodiments, the pharmaceutically acceptable salt is an alkali metal salt, ie lithium salt, sodium salt, potassium salt, alkaline earth metal salt, ie calcium salt, magnesium salt, lysine salt. N, N′-dibenzylethylenediamine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, Selected from the group consisting of hydrochloride and hydrobromide.

  In certain aspects of the first to fourth embodiments, the quinidine comprises quinidine sulfate, the dextromethorphan comprises dextromethorphan hydrobromide, and the amount of quinidine sulfate administered is about 30 mg / day to 60 mg / day. Yes, the amount of dextromethorphan hydrobromide administered is about 30 mg / day to about 60 mg / day.

  In a fifth embodiment, a method of treating pseudobulbar affect or emotional instability comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are combined A method is provided wherein the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 1.25 or less when administered in a drug form.

  In one aspect of the fifth embodiment, the pseudobulbar emotion or emotional instability is caused by a neurodegenerative disease or neurodegenerative disease, or brain injury.

  In a sixth embodiment, a method of treating neuropathic pain comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are administered in the form of a combined drug And a method is provided wherein the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 1.25 or less.

  In a seventh embodiment, a method of treating a neurodegenerative disease or neurodegenerative disease, comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are a combination drug Wherein the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 1.25 or less.

  In one aspect of the seventh embodiment, the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

  In an eighth embodiment, a method of treating brain injury comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are administered in the form of a combination drug, A method is provided wherein the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 1.25 or less.

  In an aspect of the eighth embodiment, the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event, hypoxic event, and neuronal cell death.

  In certain aspects of the fifth to eighth embodiments, the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 0.75 or less.

  In certain aspects of the fifth to eighth embodiments, the amount of quinidine administered is about 20 mg / day to about 45 mg / day, and the amount of dextromethorphan administered is about 20 mg / day to about 60 mg / day. .

  In certain aspects of the fifth to eighth embodiments, at least one of quinidine and dextromethorphan is in the form of a pharmaceutically acceptable salt.

  In certain aspects of the fifth to eighth embodiments, the pharmaceutically acceptable salt is an alkali metal salt, ie lithium salt, sodium salt, potassium salt, alkaline earth metal salt ie calcium salt, magnesium salt, lysine salt. N, N′-dibenzylethylenediamine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, Selected from the group consisting of hydrochloride and hydrobromide.

  In certain aspects of the fifth to eighth embodiments, the quinidine comprises quinidine sulfate, the dextromethorphan comprises dextromethorphan hydrobromide, and the amount of quinidine sulfate administered is from about 30 mg / day to about 60 mg / day. And the amount of dextromethorphan hydrobromide administered is about 30 mg / day to about 60 mg / day.

  In certain aspects of the fifth to eighth embodiments, the combined drug is administered once per day.

  In certain aspects of the fifth to eighth embodiments, the combined drug is administered twice or more per day.

  In a ninth embodiment, a pharmaceutical composition suitable for use in the treatment of pseudobulbar affect or emotional instability comprising a tablet or capsule, wherein the tablet or capsule comprises dextromethorphan and quinidine. A composition having a weight ratio of dextromethorphan to quinidine of about 1: 1.25 or less is provided.

  In an aspect of the ninth embodiment, the pseudobulbar emotion or emotional instability is caused by a neurodegenerative disease or neurodegenerative disease, or brain injury.

  In a tenth embodiment, a pharmaceutical composition suitable for use in the treatment of neuropathic pain, comprising a tablet or capsule, said tablet or capsule comprising dextromethorphan and quinidine, Compositions are provided wherein the weight ratio of quinidine is about 1: 1.25 or less.

  In an eleventh embodiment, a pharmaceutical composition suitable for use in the treatment of a neurodegenerative disease or neurodegenerative disease, comprising a tablet or capsule, said tablet or capsule comprising dextromethorphan and quinidine, Compositions are provided wherein the weight ratio of lomethorphan to quinidine is about 1: 1.25 or less.

  In one aspect of the eleventh embodiment, the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

  In a twelfth embodiment, a pharmaceutical composition suitable for use in brain injury, comprising a tablet or capsule, said tablet or capsule comprising dextromethorphan and quinidine, wherein the weight ratio of dextromethorphan and quinidine A composition is provided wherein is about 1: 1.25 or less.

  In an aspect of the twelfth embodiment, the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event, hypoxic event, and neuronal cell death.

  In certain aspects of the ninth to twelfth embodiments, the weight ratio of dextromethorphan to quinidine is about 1: 0.75 or less.

  In certain aspects of the ninth to twelfth embodiments, quinidine is present in an amount from about 20 mg to about 45 mg and dextromethorphan is present in an amount from about 20 mg to about 60 mg.

  In an aspect of the ninth to twelfth embodiments, at least one of quinidine and dextromethorphan is in the form of a pharmaceutically acceptable salt.

  In certain aspects of the ninth to twelfth embodiments, the pharmaceutically acceptable salt is an alkali metal salt, i.e. lithium salt, sodium salt, potassium salt, alkaline earth metal salt, i.e. calcium salt, magnesium salt, lysine salt. N, N′-dibenzylethylenediamine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, Selected from the group consisting of hydrochloride and hydrobromide.

  In certain aspects of the ninth to twelfth embodiments, the quinidine comprises quinidine sulfate, the dextromethorphan comprises dextromethorphan hydrobromide, and the quinidine sulfate is present in an amount of about 30 mg to about 60 mg, Dextromethorphan hydrobromide is present in an amount of about 30 mg to about 60 mg.

  In a thirteenth embodiment, the use of dextromethorphan and quinidine in the preparation of a medicament for treating pseudobulbar affect or emotional instability, said medicament comprising a capsule or tablet, wherein dextromethorphan and Use is provided wherein quinidine is present in the capsule or tablet in a weight ratio of dextromethorphan to quinidine of no more than 1: 1.25.

  In one aspect of the thirteenth embodiment, the pseudobulbar affect or emotional instability is caused by a neurodegenerative disease or neurodegenerative disease, or brain injury.

  In a fourteenth embodiment, the use of dextromethorphan and quinidine in the preparation of a medicament for treating neuropathic pain, said medicament comprising a capsule or tablet, wherein dextromethorphan and quinidine are said capsules. Uses are provided that are present in a weight ratio of dextromethorphan and quinidine in the drug or tablet of no more than 1: 1.25.

  In a fifteenth embodiment, the use of dextromethorphan and quinidine in the preparation of a neurodegenerative disease or a medicament for treating a neurodegenerative disease, said medicament comprising a capsule or a tablet, wherein dextromethorphan and quinidine are A use is provided wherein the capsule or tablet is present in a weight ratio of dextromethorphan to quinidine of no more than 1: 1.25.

  In one aspect of the fifteenth embodiment, the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.

  In a sixteenth embodiment, the use of dextromethorphan and quinidine in the preparation of a medicament for treating brain injury, said medicament comprising a capsule or tablet, wherein dextromethorphan and quinidine are said capsule or Uses are provided that are present in tablets in a weight ratio of dextromethorphan and quinidine of 1: 1.25 or less.

  In an aspect of the sixteenth embodiment, the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event, hypoxic event, and neuronal cell death.

  In certain aspects of the thirteenth through sixteenth embodiments, dextromethorphan and quinidine are present in the capsule or tablet in a weight ratio of dextromethorphan and quinidine of no more than 1: 0.75.

  In an aspect of the thirteenth through sixteenth embodiments, at least one of quinidine and dextromethorphan is in the form of a pharmaceutically acceptable salt.

  In certain aspects of the thirteenth to sixteenth embodiments, the pharmaceutically acceptable salt is an alkali metal salt, i.e. lithium salt, sodium salt, potassium salt, alkaline earth metal salt, i.e. calcium salt, magnesium salt, lysine salt. N, N′-dibenzylethylenediamine salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, Selected from the group consisting of hydrochloride and hydrobromide.

  In certain aspects of the thirteenth through sixteenth embodiments, the quinidine comprises quinidine sulfate, the dextromethorphan comprises dextromethorphan hydrobromide, and the quinidine sulfate is present in an amount of about 30 mg to about 60 mg, Dextromethorphan hydrobromide is present in an amount of about 30 mg to about 60 mg.

  In certain aspects of the thirteenth through sixteenth embodiments, quinidine is present in an amount from about 20 mg to about 45 mg and dextromethorphan is present in an amount from about 20 mg to about 60 mg.

FIG. 1 is a box plot of a CNS-LS score for clinical study # 4. The distribution of CNS-LS scores is symmetric and contains only one outlier. These distributions support the use of ANCOVA (covariance analysis) for analysis of CNS-LS scores. Differences in mean improvement in CNS-LS scores adjusted for institutional and baseline CNS-LS scores, as expected in the study protocol, were calculated using linear regression according to Frison and Pocock's ANCOVA method. analyzed. The results of this analysis are shown in Table 30. Additional analysis results that were not adjusted at all or adjusted only for the baseline CNS-LS score are also shown in this table. FIG. 2 is a plot showing the adjusted mean reduction in CNS-LS score for the three treatment groups obtained from the primary efficacy analysis of the ITT population in clinical study # 4. The decrease in CNS-LS score below the horizon is statistically significant at 30DM / 30Q at the required level of significance. FIG. 3 shows the nature of subjects who participated in clinical study # 5 by the MTD group. FIG. 4 shows the average sleep rating from the subject's diary for subjects participating in clinical study # 5. FIG. Average current pain intensity assessment from subject diary for subjects participating in Clinical Study # 5. FIG. Average activity assessment of subjects participating in clinical study # 5 from subject diary. FIG. Average pain assessment of subjects participating in clinical study # 5 from subject diary.

  The following description and examples illustrate preferred embodiments of the invention in detail. Those skilled in the art will appreciate that there are many variations and modifications of this invention that fall within the scope of this invention. Accordingly, the description of a preferred embodiment should not be construed as limiting the scope of the invention.

Emotional instability or pseudobulbaric affect can be found in stroke (House et al., BMJ, 1989, 298, pp. 991-4), multiple sclerosis (MS) (Cotrell et al., J. Neurol. Psychopathol., 1926, volume 7, pages 1-30; Feinstein et al., Arch. Neurol., 1997, volume 54, pages 1116-21, amyotrophic lateral sclerosis (ALS) (Miller et al., Neurol). 1999, vol. 52, pages 1311-23; Jackson et al., Semin. Neurol., 1998, vol. 18, pages 27-39; Poeck, K., “Pathology of emotional hazards.
associated with brain damage. "Source: P.I. J. et al. Vinken, G.M. W. Bruyn ed., "Handbook of Clinical Neurology", Amsterdam, North-Holland Publishing Company, 1969, pp. 343-67), Alzheimer's disease (Starkstein et al., J. Neurol. -64), and traumatic brain injury (Brooks, N., Acta Neurochirurica, Extra 44, 1988, 59-64). Studies have shown that up to 50% of ALS patients develop pseudobulbar emotions (Gallagher, JP, Acta Neurol. Scand., 1989, 80, 114-7). ).

  Emotional instability or pseudobulbar affect can be viewed in terms of nerve damage as a disjunction syndrome that occurs as a result of loss of contact with the brainstem or cerebellum from the cortex (Wilson SAK, J. Neurol). Psychopathol., 1924, volume IV, pages 299-333; Parvivzi et al., Brain, 2001, volume 124, pages 1708-19). At the level of neurotransmitters, disruption of the ascending and descending serotonergic pathways that occur in the brainstem, and dysregulation of dopaminergic projections to the striatum and cortex (Andersen et al., Stroke, 1994, 25, 1050-2; Ross et al., J. Nerv. Ment. Dis., 1987, 175, 165-72; Shaw et al., Brain Sciences in Psychiatry, London: Butterworth, 1982; Udaka et al., Arch. Neurol., 1984, 41, 1095-6).

  A series of evidence suggests that pseudobulbar affect can be modulated by pharmacological intervention. In 1979, Wolf reported that levodopa was effective in pathologically laughing subjects (Wolf et al., Neurol., 1979, Vol. 29, pages 1435-6). However, in follow-up, only 10 of 25 subjects responded well enough to treatment (Udaka et al., Arch. Neurol., 1984, 41, 1095-6). page). Other drugs such as amantadine, imipramine, desipramine, nortriptyline, amitriptyline, sertraline, fluoxetine, levodopa, methylphenidate, and thyrotropin-releasing hormone have been reported to improve symptoms (Dark et al., Austr. Zeal. J. Psychiatry, 1996, 30, 472-9; Ianoccon et al., Clin. Neuropharm., 1996, 19, 532-5).

  The best known therapy to date for treating emotional instability is to use the drugs amitriptin, amantadine, and levodopa. Udaka et al., Arch. Neurol. 1984, 41, 1095-1096, Schiffer et al. Engl. J. et al. Med. , 1985, 312, pp. 1480-1482 suggest that these compounds may be effective in helping alleviate morbid emotional expression in some patients. However, none of these prior art drugs are effective for all patients, and even patients who have benefited from some degree usually lose effectiveness without far reaching effective healing. Is specified. The general practice of many clinical neurologists prescribes amitriptin and amantadine one at a time, hoping that one of them can improve the patient's condition at some level. However, both are insufficient to provide effective healing. Furthermore, levodopa is not satisfactory because it has other effects and is a relatively powerful drug.

  ALS is a neurodegenerative disease caused by progressive loss of upper and lower motor neurons. Up to 50 percent of ALS patients show emotional instability and are more common in patients with spherical ALS (Gallagher JP, Acta Neurol. Scand., 1989, 80, 114-7). Based on the view that excitotoxicity associated with impaired recirculation of glutamate may contribute to the pathogenesis of ALS, riluzole, a glutamate release inhibitor, has been used in the treatment of ALS (Jerusalem et al., Neurology). 1996, 47, S218-20; Double A., Neurology, 1996, 47, S233-41). Riluzole prolongs life to some extent but does not lead to symptom improvement (Bensimon et al., N. Eng. J. Med., 1994, 330, 585-91; Kwiecinski H, Neurol. Neurochir. Pol. 2001, volume 35, pages 51-9).

  Because the excitotoxic process involving glutamate may be implicated in the pathogenesis of ALS, several researchers may try to alleviate or prevent the progression of ALS by administering dextromethorphan (DM) It was. DM is a non-competitive antagonist of N-methyl-D-aspartate-sensitive ion channel-coupled glutamate receptors and acts by reducing the level of excitatory activity. However, DM is extensively metabolized to dextrorphan (DX) and many other metabolites. Cytochrome P450 2D6 (CYP2D6) is an important enzyme responsible for the production of DX from DM. Some people, 5-10% whites, have reduced activity of this enzyme (Hildebrand et al., Eur. J. Clin. Pharmacol., 1989, 36, 315-318). Such persons are referred to as the “low metabolic group” of DM against the vast majority of people referred to as the “high metabolic group” of DM (Vetticaden et al., Pharm. Res., 1989, Vol. 6, 139). page).

  Many in vitro studies have been undertaken to determine the types of drugs that inhibit CYP2D6 activity. Quinidine (Q) is one of the most potent drugs studied (Inaba et al., Br. J. Clin. Pharmacol., 1986, Vol. 22, pages 199-200). These observations led to the hypothesis that the DM concentration in plasma may increase when taken simultaneously with Q.

  Many chronic illnesses other than emotional instability are also associated with symptoms that are very difficult to treat, are safe, non-addictive, and often do not respond well to non-steroidal drugs. Diseases such as refractory cough do not respond favorably to conventional drugs and are generally treated with drugs such as codeine, morphine, and the anti-inflammatory steroid prednisone. These drugs are unacceptable for long-term treatment due to dangerous side effects, long-term risks to patient health, or risk of addiction. There is no satisfactory treatment for severe itching and rashes associated with dermatitis. Drugs such as prednisone and even tricyclic antidepressants have been used in topical applications but do not appear to provide substantial and always the same relief. Chronic pain due to diseases such as stroke, cancer and trauma, as well as neuropathic pain resulting from diseases such as diabetes and herpes zoster (zoster), are problems that resist treatment. Neuropathic pain includes, for example, diabetic neuropathy, postherpetic neuralgia, phantom limb pain, trigeminal neuralgia, and sciatica. Postherpetic neuralgia (PHN) is a complication of herpes zoster and occurs in about 10 percent of patients with herpes zoster. The incidence of PHN increases with age. Diabetic neuropathy is a common complication of diabetes and increases with disease duration. These types of neuropathic pain are described as uninterrupted burning pains, often combined with stinging, tingling and toothache. The skin can be sensitive to light touch and clothing with a feeling of sensory abnormalities. Pain can be exacerbated by activity, temperature changes, and emotional disturbances. Pain can be so severe that it interferes with daily activities or causes sleep problems or loss of appetite. The mechanism by which these types of pain are born is not well understood, but degeneration of myelinated nerve fibers may be involved. In diabetic neuropathies, large and small nerve fibers have been found to decline, reducing the threshold for tolerance to heat sensitivity, pain, and vibration. Small and large fiber dysfunction is more severe when pain occurs in the lower limbs. Most of the physiological measurements of nerves that can be done routinely in patients with neuropathic pain indicate that nerve conduction slows down over time. To date, the treatment of neuropathic pain has not been successful without exception. Chronic pain is estimated to affect millions.

  Dextromethorphan has been found to be widely used as a cough syrup, safe enough for the human body, and used as an over-the-counter medicine that does not require a doctor's prescription. Dextromethorphan is well tolerated in oral dosage forms, alone or in combination with quinidine, up to 120 milligrams per day (mg), even when given fairly low doses (eg 30 mg / day). Beneficial effects can be observed (Smith US Pat. No. 5,206,248).

  The chemistry for dextromethorphan and its analogs is described by Rodd, E .; H. Ed. “Chemistry of Carbon Compounds”, Elsevier Publ. New York, 1960; Goodman and Gilman, “Pharmacological Basis of Therapeutics”; Choi, Brain Res. 1987, 403, 333-336; and U.S. Pat. No. 4,806,543. Its chemical structure is as follows.

デキストロメトルファンは、（＋）−３−メトキシ−Ｎ−メチルモルフィナンの俗名である。これは、モルヒネ様オピオイドの右旋性類似体である分子群の１種である。用語「アヘン剤（オピエート）」とは、モルヒネやコデインなど、アヘンから得られる薬物を指す。用語「オピオイド」は、より広義である。これには、アヘン剤、ならびに哺乳動物において鎮痛剤および鎮静剤として作用する、天然または合成の他の薬物が含まれる。

Dextromethorphan is the common name for (+)-3-methoxy-N-methylmorphinan. This is one of a group of molecules that are dextrorotatory analogs of morphine-like opioids. The term “opiate” refers to drugs obtained from opium, such as morphine and codeine. The term “opioid” is broader. This includes opiates and other natural or synthetic drugs that act as analgesics and sedatives in mammals.

  Many of the addictive analgesic opiates, such as morphine, codeine, and heroin, are levorotatory stereoisomers (which rotate the polarization so-called counterclockwise). These have four molecular rings in the configuration known as the “morphinan” structure shown below.

この図では、示してあるとおり、炭素原子に従来どおりに番号を付け、９番および１３番の炭素原子に結合している楔形の結合は、この結合がモルフィナン構造中の他の３つの環からなる平面から上に飛び出していることを示す。この基本構造（モルヒネを含む）の多くの類似体は、４番と５番の炭素原子間の架橋原子（酸素など）によって追加の環が形成されている五環式化合物である。

In this figure, as shown, the wedge-shaped bond, which is conventionally numbered to carbon atoms and bonded to carbon atoms 9 and 13, is linked from the other three rings in the morphinan structure. It shows that it is popping up from the plane. Many analogs of this basic structure (including morphine) are pentacyclic compounds in which an additional ring is formed by a bridging atom (such as oxygen) between the 4th and 5th carbon atoms.

  Many dextrorotary morphine analogs are much less addictive than levorotatory compounds. Some of these dextrorotatory analogs including dextromethorphan and dextrorphan are enantiomers of the morphinan structure. In these enantiomers, the rings extending from the 9th and 13th carbon atoms extend in the opposite direction to that shown in the above structure.

  Without being limited to any particular mechanism of action, dextromethorphan has been found to have at least three different receptor activities that affect central nervous system (CNS) neurons. First, it acts as an antagonist of N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is one of three major types of excitatory amino acid (EAA) receptors in CNS neurons. Since NMDA receptor activation causes neurons to release excitatory neurotransmitter molecules (primarily glutamate, amino acids), the blocking activity of dextromethorphan at these receptors is responsible for the excitation of neurons with these receptors. Reduce the activity level. Dextromethorphan is thought to act at the phencyclidine (PCP) binding site that is part of the NMDA receptor complex. Dextromethorphan has a relatively weak NMDA antagonist activity, especially compared to drugs such as MK-801 (dizocilpine) and phencyclidine. Thus, when administered at an approved dosage, dextromethorphan is a toxic side effect caused by potent NMDA antagonists such as MK-801 and PCP (Olney, US Pat. No. 5,034,400). It is thought that it does not bring about.

  Dextromethorphan also functions as an agonist (agonist) of certain inhibitory receptors. Unlike EAA receptors, when inhibitory receptors are activated, release of excitatory neurotransmitters by affected cells is inhibited. Initially, these inhibitory receptors were called σ opiate receptors. However, questions have arisen about whether they are actually opiate receptors, so they are now commonly referred to as sigma (σ) receptors. Subsequent experiments have shown that dextromethorphan binds to another type of inhibitory receptor that is different from, but closely related to, the σ receptor. Evidence that a non-sigma inhibitory receptor exists and binds to dextromethorphan is known that some molecules that bind to sigma receptor have dextromethorphan and inhibitory receptors It cannot be completely blocked from binding to different types of neurons (Musacchio et al., Cell Mol. Neurobiol., June 1988, Vol. 8 (2), pp. 149-56; Musacchio et al., J. Pharmacol. Exp. Ther., November 1988, 247 (2), 424-31; Craviso et al., Mol. Pharmacol., May 1983, 23 (3), 629-40; Craviso et al., Mol. Pharmacol., May 1983, Volume 23 (3), 61 To 28 pages;. And Klein et al., Neurosci.Lett, 2 May 13, 1989, the first 97 Volume (1-2), the first 175 to 80 pages). These receptors are commonly referred to in the scientific literature as “high affinity dextromethorphan receptors” or simply “DM receptors”. As used herein, the phrase “dextromethorphan-binding inhibitory receptor” includes an excitatory neuron by an affected cell that has an affinity binding reaction with dextromethorphan and is activated by dextromethorphan. Both sigma and non-sigma receptors that suppress transmitter release are included (Largent et al., Mol. Pharmacol., December 1987, 32 (6), 772-84).

Dextromethorphan also reduces calcium ion (Ca ⁺⁺ ) uptake by neurons. Calcium uptake occurs when nerve impulses (impulses) are transmitted and involves at least two different types of channels known as N-type and L-type channels. Dextromethorphan significantly suppresses calcium uptake in certain types of cultured neurons (synaptosomes) that contain N-type channels, and is not as strong in other cultured neurons that contain L-type channels (PC12 cells) Calcium uptake was suppressed (Carpenter et al., Brain Res., Jan. 26, 1988, 439 (1-2), 372-5).

  A growing body of evidence suggests that dextromethorphan has potential therapeutic potential for treating several neuronal diseases (Zhang et al., Clin. Pharmacol. Ther., 1992). 51, 647-655; Palmer GC, Curr. Drug Targets, 2001, Volume 2, pages 241-271; and Liu et al., J. Pharmacol. Exp. Ther., 2003, 21. Vol., Page 21; Kim et al., Life Sci., 2003, 72, 769-783). Pharmacological studies have demonstrated that DM is a noncompetitive NMDA antagonist with neuroprotective, anticonvulsant, and antinociceptive activity in many experimental models (Desmeules et al., J. Biol. Pharmacol. Exp. Ther., 1999, 288, 607-612). In addition to acting as an NMDA antagonist, DM and its primary metabolite, dextrorphan, bind to the σ-1 site, inhibit calcium entry channels, and interact with high voltage-gated sodium channels (Dickenson). Neuropharmacology, 1987, 26, 1235-1238; Carpenter et al., Brain Res., 1988, 439, 372-375; Netzer et al., Eur. J. Pharmacol., 1993, 238, 209-216). Recent reports indicate that DM's further neuroprotective mechanisms may involve blocking the inflammatory response associated with several neurodegenerative diseases including Parkinson's disease and Alzheimer's disease (Liu). Et al., J. Pharmacol. Exp. Ther., 2003, 21, 21). The potential efficacy of DM as a neuroprotective agent is found in amyotrophic lateral sclerosis (Gredal et al., Acta Neurol. Scand., 1997, 96, 8-13; Blin et al., Clin. Neuropharmacol. 1996, 19: 189-192), Huntington's disease (Walker et al., Clin. Neuropharmacol., 1989, 12: 322-330), and Parkinson's disease (Chase et al., J. Neurol. , 2000, vol. 247, volume 2, pages 36-42), limited clinical trials of patients. DM has also been investigated in patients with various types of neuropathic pain (Mcquay et al., Pain, 1994, 59, 127-133; Vinik AI, Am. J. Med., 1999). 107, 17S-26S; Weinbroum et al., Can. J. Anaesth., 2000, 47, 585-596; Sang et al., Anesthesiology, 2002, 96, 1053-1061. Heiskanen et al., Pain, 2002, 96, 261-267; Ben Abraham et al., Clin. J. Pain, 2002, 18, 282-285; Sang CN, J. Pain Symptom Manage., 2000, Vol. 19, Vol. S21-25 pages). Although the pharmacological profile of DM shows clinical efficacy, most clinical trials are disappointing with less apparent efficacy of DM compared to placebo treatment.

  Several researchers have suggested that the limited benefits seen in DM clinical trials are associated with rapid metabolism in the liver that limits systemic drug concentrations. In one trial of a patient with Huntington's disease, plasma concentrations were not detected in some of the patients after taking DM at 8 times the maximum antitussive dose (Walker et al., Clin. Neuropharmacol., 1989, 12th. Volume, pages 322-330).

  As discussed above, DM is extensively O-demethylated to dextrorphan by catalyzing CYP2D6 in the liver. This enzyme is the same enzyme responsible for hydroxylation of the human polymorphic debrisoquine (Schmid et al., Clin. Pharmacol. Ther., 1985, 38, 618-624). An alternative route is to generate 3-methoxymorphinan primarily through CYP3A4 and N-demethylation (Von Moltke et al., J. Pharm. Pharmacol., 1998, 50, 997). -10page). Both DX and 3-methoxymorphinan are further demethylated to 3-hydroxymorphinan, which is then glucuronidated. The metabolic pathway that converts DM to DX is dominant in the majority of people and is the principle that DM is used as a probe for individuals with high and low metabolizers of CYP2D6 (Kupfer et al., Lancet). 1984, Vol. 2, pages 517-518; Guttendorf et al., Ther. Drug Monitor, 1988, Vol. 10, pages 490-498). About 7% of whites show a low metabolite phenotype, while the incidence of low metabolite phenotypes is lower in Chinese and African blacks (Droll et al., Pharmacogenetics, 1998, Vol. 8, Pp. 325-333). A study investigating the ability of DM's high and low metabolizers to increase pain thresholds found that DM's anti-nociceptive effects were significant in low metabolizers but not in high metabolizers (Desmeules et al., J. Pharmacol. Exp. Ther., 1999, 288, 607-612). This result is consistent with the direct influence of the parent DM on the neuromodulation rather than the DX metabolite.

  One approach to increasing systemically available DM is to administer the CYP2D6 inhibitor quinidine together to protect DM from metabolism (Zhang et al., Clin. Pharmacol. Ther. 1992, 51, pages 647-655). Administration of quinidine can convert a subject with a high metabolite phenotype to a phenotype with a low metabolite (Inaba et al., Br. J. Clin. Pharmacol., 1986, Vol. 22, 199-200. page). When this combination therapy was tested in patients with amyotrophic lateral sclerosis, it seemed to have a symptomatic effect on the symptoms of pseudobulbar affect (Smith et al., Neurol., 1995, 54th). Volume, page 604). Combination treatment with DM and quinidine also appeared to be effective in patients with chronic pain that was not well controlled with other drugs. This observation suggests that DM was effective in increasing pain thresholds in hypometabolists and high metabolizers given quinidine but not in high metabolizers (Desumeles et al. J. Pharmacol. Exp. Ther., 1999, 288, 607-612). To date, most studies have used doses of quinidine ranging from 50-200 mg to inhibit CYP2D6-mediated drug metabolism, but identify the minimum dose of quinidine to inhibit the enzyme No research has been done.

  For very complex interactions between different types of neurons with different people at different receptors, dextromethorphan, and other types of molecules that can interact with some or all of these same types of receptors The cross affinity of different types of receptors makes it very difficult to attribute the overall effect of dextromethorphan to the binding activity of any particular type of receptor. Nevertheless, dextromethorphan is thought to suppress neuronal activity through at least three molecular functions. That is, dextrometrophan reduces the activity of (excitatory) NMDA receptors, binds to certain inhibitory receptors and inhibits neuronal activity, and further calcium through N-type and L-type channels. Suppresses uptake of.

  Unlike some morphine analogs, dextromethorphan exhibits agonistic or antagonistic activity for a variety of other opiate receptors, including mu (μ) class opiate receptors and kappa (κ) class opiate receptors. Little or no. This is very important because the agonist or antagonist activity of these opiate receptors can cause undesirable side effects such as respiratory depression (impeded breathing) and inhibition of analgesia (reducing the effectiveness of analgesics). Is desirable.

  Accordingly, a drug that functions as an antagonist of the NMDA receptor and as an agonist of the dextromethorphan-binding inhibitory receptor and also has no agonist activity or antagonist activity of the μ opiate receptor or κ opiate receptor, That is, by administering dextromethorphan, at least some patients' emotional instability or pseudobulbaric emotion can be treated.

  In most people (estimated to contain about 90% of the total population of the United States), dextromethorphan has long been known to be rapidly metabolized and eliminated by the body (Ramachander et al., J. Pharm). Sci., July 1977, 66 (7), 1047-8; and Vetticaden et al., Pharm. Res., January 1989, 6 (1), 13-9). This removal is primarily due to the enzyme known as the P450 2D6 (ie IID6) enzyme, which is a member of a class of oxidases known as cytochrome P450 enzymes present at high concentrations in the liver ( Kronbach et al., Anal. Biochem., April 1987, 162 (1), pages 24-32; and Dayer et al., Clin. Pharmacol. Ther., January 1989, 45 (1), vol. 34-40 pages). In addition to dextromethorphan metabolism, P450 2D6 isoenzymes also oxidize sparteine and debrisoquine. It is known that the P450 2D6 enzyme can be inhibited by many drugs, particularly quinidine (Brin et al., Br. J. Clin. Pharmacol., August 1986, Vol. 22 (2), 194-7. Inaba et al., Br. J. Clin. Pharmacol., August 1986, 22 (2), 199-200; Brosen et al., Pharmacol. Toxicol., April 1987, 60 (4 ), Pages 312-4; Oton et al., Drug Metab. Dispos., January-February 1988, Volume 16 (1), pages 15-7; Oton et al., J. Pharmacol. Exp. Ther., October 1988, 247 (1), 242-7; Funck-Brentano et al., Br. J. Clin. Pharmacol., April 1989, 27 (4), 435-44; Funck-Brentano et al., J. Pharmacol. Exp. Ther., April 1989, 249 ( 1), pages 134-42; Nielsen et al., Br. J. Clin. Pharmacol., March 1990, 29 (3), 299-304; Brolly et al., Br. J. Clin. Pharmacol. July 1989, 28 (1), 29-36).

  Patients who lack normal levels of P450 2D6 activity are classified as “low metabolizers” in the medical literature, and physicians are generally warned to be careful about administering various drugs to such patients. “If oxidative biotransformation of these compounds is reduced in low-metabolites (PMs), excessive drug accumulation can lead to increased peak drug levels and possibly reduced production of active metabolites. Yes ... patients with PM phenotype have an increased risk of annoying effects that may be heavy ... "(Guttendorf et al., Ther. Drug Monit., 1988, 10 (4), 490-8, 490). Therefore, physicians are cautious about administering quinidine to patients, and rather than using drugs like quinidine to control the rapid removal of dextromethorphan, researchers working in this area Is known to cause various problems, but patients are receiving very high doses (eg 750 mg / day) of dextromethorphan (Walker et al., Clin Neuropharmacol., August 1989, 12 (4), 322-30; and Alberts et al., Stroke, August 1991, 22 (8), 1075-7).

  Dextromethorphan is a weak, non-competitive NMDA receptor antagonist that binds with moderate to high affinity to the phencyclidine site of the receptor complex. However, DM has additional unique pharmacological properties. Binding studies have shown that DM is a high affinity sigma1 ligand, where it was initially proposed that DM act as an antagonist (Torella et al., TiPS, 1989, 10, 501-7), and more recently it has been proposed to act as an agonist (Maurice et al., Brain Res. Brain Res. Rev., 2001, 37, 116). ~ 32 pages). The sigma ligand also modulates the NMDA response (Debonnel et al., Life Sci., 1996, 58, 721-34). Because of its inhibitory effect on glutamate, many researchers have treated ALS patients with DM in the hope of alleviating or preventing the disease (Askmark et al., J. Neurol. Neurosurg. Psychiatry, 1993, 56, 197-200; Hollander et al., Ann. Neurol., 1994, 36, 920-4; and Blin et al., Clin. Neuropharmacol., 1996, 19 Volume, pages 189-92). These trials, or because of the rapid and massive metabolism of DM that occurs in about 90 percent of whites (called hypermetabolites), showed no benefit (Hildebrand et al., Eur. J. Clin. Pharmacol., (See 1989, volume 36, pages 315-8).

DM metabolism is primarily mediated by CYP2D6 in hypermetabolites. This can be avoided by administering quinidine, a selective CYP2D6 inhibitor, together with a Q dose of 1/10 ¹ to 1/10 ^1.5 of that used to treat cardiac arrhythmias (Schadel et al. J. Clin. Psychopharmacol., 1995, Vol. 15, pp. 263-9). DM blood levels increased linearly with DM dose after co-administration with Q, but in most subjects who received DM alone, even at high doses, detection (Zhang et al., Clin. Pharmac. & Therap., 1992, 51, 647-55). Thus, the plasma levels observed in these individuals are the same as those observed in individuals (low metabolizers) with a minority phenotype with reduced levels of P450 2D6 due to genetic polymorphism. It is very similar. Unexpectedly, during a DM and Q study in ALS patients, the patients reported that their emotional instability improved during treatment. Later, in a placebo-controlled crossover study (N = 12) conducted to investigate this, emotional instability was suppressed when DM and Q were administered in combination to ALS patients (P <0 vs. placebo). 0.001) (Smith et al., Neurology, 1995, 45, A330).

  Rapid dextromethorphan removal can be overcome by administering quinidine together with dextromethorphan (Smith US Pat. No. 5,206,248). The chemical structure of quinidine is as follows:

キニジンの同時投与は、少なくとも２つの明確な有益な効果を有する。第１に、キニジンは、血中を循環するデキストロメトルファンの量を大幅に増加させる。さらに、キニジンはまた、より一定かつ予測可能なデキストロメトルファン濃度を与える。デキストロメトルファン、またはキニジンとデキストロメトルファンの同時投与、および血漿濃度に対するキニジンの影響に関係する研究は、特許文献（Ｓｍｉｔｈの米国特許第５，１６６，２０７号、米国特許第５，８６３，９２７号、米国特許第５，３６６，９８０号、米国特許第５，２０６，２４８号、および米国特許第５，３５０，７５６号明細書）に記載されている。

Co-administration of quinidine has at least two distinct beneficial effects. First, quinidine greatly increases the amount of dextromethorphan circulating in the blood. In addition, quinidine also provides a more constant and predictable dextromethorphan concentration. Studies involving dextromethorphan, or co-administration of quinidine and dextromethorphan, and the effect of quinidine on plasma concentrations are described in the patent literature (Smith US Pat. No. 5,166,207, US Pat. No. 5,863,927). No. 5,366,980, US Pat. No. 5,206,248, and US Pat. No. 5,350,756).

  The discovery that dextromethorphan can reduce the inner emotions and external symptoms of emotional instability or pseudobulbar emotions in some patients with progressive neurological disease Also, during strokes and other ischemic (low blood flow) or hypoxic (hypoxic) events that cause neuronal cell death or damage to limited areas of the brain, in car, motorcycle or bicycle accidents, or It suggests that it may also be useful to help some patients suffering from emotional instability due to other causes, such as head injury or trauma that can occur due to gunshot wounds.

  In addition, the results obtained so far also suggest that dextromethorphan is likely to be useful in treating some cases of emotional instability due to administration of other drugs. For example, various steroids such as prednisone are widely used to treat autoimmune diseases such as lupus. However, prednisone can be found in many patients, ranging from mild but noticeably increased levels of moodiness and depression to severely worsened emotional instability that can interfere with the patient's work, housework, or personal affairs. Accompanying adverse events to emotional state.

  In addition, when combined with quinidine, dextromethorphan is caused by a variety of other problems, such as “premenstrual syndrome” (PMS), Tourette's syndrome, and emotional eruptions that occur in people with certain types of psychosis. Or the accompanying external emotional expression or internal emotion can be reduced. These problems may not be considered clinically emotional instability, but are accompanied by symptoms that appear to be sufficiently similar to emotional instability, and dextromethorphan is It is suggested that it can be an effective therapeutic agent for at least some patients suffering from such problems.

  One important feature of the preferred embodiment therapy is that it reduces emotional instability without being sedated or otherwise significantly hindering patient awareness or agility. It is to act on. As used herein, “serious hindrance” refers to the clinical level (which will draw the explicit attention of a physician or psychologist), or the personal or social level (so much that impairs a person's ability to drive a car) It refers to an adverse event that may become serious (for example, by causing sufficiently severe sleepiness). In contrast, the types of very mild side effects that can be caused by over-the-counter medications such as cough syrup containing dextromethorphan when used at recommended doses are not considered serious hindrances .

  The degree of prophylactic or therapeutic dose of dextromethorphan combined with quinidine in the treatment of the acute or chronic phase of emotional instability or other chronic illness depends on the specific cause of the illness, the severity of the illness, and It may vary depending on the route of administration. The dose and / or frequency of administration may also vary according to the individual patient's age, weight and responsiveness.

  In general, it is preferred that dextromethorphan and quinidine be administered as a combined drug or administered substantially simultaneously in separate drugs. The preferred weight ratio of dextromethorphan to quinidine is about 1: 1.5 or less, preferably about 1: 1.45, 1: 1.4, 1: 1.35, 1: 1.3 or less, more preferably About 1: 1.25, 1: 1.2, 1: 1.15, 1: 1.1, 1: 1.05, 1: 1, 1: 0.95, 1: 0.9, 1: 0 .85, 1: 0.8, 1: 0.75, 1: 0.7, 1: 0.65, 1: 0.6, 1: 0.55, 1: 0.5 or less. However, in certain embodiments, the dosage ratio of dextromethorphan to quinidine is greater than about 1: 1.5, for example, about 1: 1.6, 1: 1.7, 1: 1.8, 1: A dosage of 1.9, 1: 2 or more may be preferred. Similarly, in certain embodiments, dosages wherein the ratio of dextromethorphan to quinidine is less than about 1: 0.5, such as about 1: 0.45, 1: 0.4, 1: 0.35, 1: 0.3, 1: 0.25, 1: 0.2, 1: 0.15, 1: 0.1 or less may be preferable. When dextromethorphan and quinidine are administered at a preferred ratio of 1: 1.25 or less, it is generally less than 50 mg at a time, more preferably about 45 mg, 40 mg, 35 mg or less, most preferably about 30 mg, 25 mg, 20 mg. Preferably the following quinidine is administered. This combination (or twice a day, three times a day, four times a day, or more frequently, at a preferred ratio of 1: 1.25 or less, as given to patients at a preferred dosage level per day Are also preferred, eg 60 mg quinidine and 60 mg dextromethorphan per day, each dose containing 30 mg quinidine and 30 mg dextromethorphan Giving 50 mg quinidine and 50 mg dextromethorphan per day, giving 2 doses each containing 25 mg quinidine and 25 mg dextromethorphan; 1 40 mg of quinidine and 40 mg of dextromethorphan per day for 20 doses each 2 times containing g quinidine and 20 mg dextromethorphan; 30 mg quinidine and 30 mg dextromethorphan per day, each dose of 15 mg quinidine and 15 mg dextromethorphan 2 doses containing 20 mg quinidine and 20 mg dextromethorphan per day, 2 doses each containing 10 mg quinidine and 10 mg dextromethorphan It is preferable. The total amount of dextromethorphan and quinidine in the combination is the number of doses administered per day to give the patient an appropriate total daily dosage while maintaining a preferred ratio of 1: 1.25 or less. You may adjust according to. These ratios are particularly preferred for the treatment of emotional instability and neuropathic pain.

  In general, the total daily dose when combining dextromethorphan and quinidine for the diseases described herein is about 10 mg or less to about 200 mg or more of dextromethorphan and about 1 mg or less to about 150 mg or more. Preferably in combination with quinidine; preferably from about 15 mg or 20 mg to about 65 mg, 70 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or 190 mg Of dextromethorphan and about 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg to about 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 m , 120 mg, 130 mg, or 140 mg of quinidine; more preferably about 25 mg, 30 mg, 35 mg, or 40 mg to about 55 mg or 60 mg of dextromethorphan and about 25 mg, 30 mg, or 35 mg to about 40 mg, 45 mg, Or in combination with 50 mg quinidine. In a particularly preferred embodiment, the daily dose of dextromethorphan (DM) and quinidine (Q) is 20 mg DM and 20 mg Q; 20 mg DM and 30 mg Q; 20 mg DM and 40 mg Q; 20 mg DM and 50 mg Q; 20 mg DM and 60 mg Q; 30 mg DM and 20 mg Q; 30 mg DM and 30 mg Q; 30 mg DM and 40 mg Q; 30 mg DM and 50 mg Q; 30 mg DM 40 mg DM and 20 mg Q; 40 mg DM and 30 mg Q; 40 mg DM and 40 mg Q; 40 mg DM and 50 mg Q; 40 mg DM and 60 mg Q; 50 mg DM and 20 mg Q: 50 mg DM and 30 mg Q; 50 mg DM and 40 mg Q; 50 mg DM and 50 mg Q; 50 m It is or 60mg of DM and 60mg of Q; the DM and 50mg of Q; 60mg of DM and 20mg of Q; 60mg of DM and 30mg of Q; 60mg of DM and 40mg of Q; 60mg of DM and 50mg of Q. It may be administered once per day or in several divided doses (two, three, four, or more times per day).

  The daily dose for emotional instability is preferably a combination of about 20 mg to about 60 mg dextromethorphan and about 20 mg to about 60 mg quinidine in single or divided doses. A particularly preferred daily dose for emotional instability is about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg dextromethorphan in a single or divided dose , About 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg in combination with quinidine; about 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg , Or 40 mg dextromethorphan with about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg quinidine; about 40 mg, 41 mg, 42 mg, 43 g, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, or 50 mg of dextromethorphan combined with about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg of quinidine Or about 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, or 60 mg of dextromethorphan and about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, Combination with 29 mg or 30 mg quinidine.

  In general, the total daily dose when using dextromethorphan and quinidine in combination for chronic pain such as neuropathic pain, refractory cough, dermatitis, tinnitus, and sexual dysfunction is less than about 10 mg To about 200 mg or more of dextromethorphan and about 1 mg or less to about 150 mg or more of quinidine. The total daily dose for chronic pain such as neuropathic pain, refractory cough, dermatitis, tinnitus, and sexual dysfunction is approximately 20 mg, 21 mg, 22 mg in single or divided doses. , 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg of dextromethorphan and about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg of quinidine Combined; about 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, or 40 mg dextromethorphan and about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29mg In combination with 30 mg quinidine; about 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, or 50 mg dextromethorphan and about 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg in combination with quinidine; or about 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, or 60 mg dextromethorphan and about 20 mg, 21 mg , 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg in combination with quinidine. Similar daily doses are generally preferred for the other indications described herein.

  In the management of treatment, treatment begins with a smaller daily dose, preferably a combination of about 20 mg or 30 mg dextromethorphan and about 2.5 mg quinidine per day, to the patient's overall response. Accordingly, it is preferred to increase up to about 60 mg dextromethorphan and about 75 mg quinidine, or more. More preferably, infants, children, patients 65 years of age and older, and patients with impaired renal or liver function are given low doses initially and gradually increased based on individual response and blood levels. In general, daily doses of 20-30 mg dextromethorphan and 20-30 mg quinidine are well tolerated by most patients.

  It will be apparent to those skilled in the art that in some cases it may be preferable to administer dosages outside these preferred ranges. In addition, it is specifically noted that the ordinary skilled clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in view of individual patient responses.

  Any suitable route of administration may be used to provide the patient with an effective dose of dextromethorphan and quinidine combined. For example, administration forms such as oral, rectal, transdermal, parenteral (subcutaneous, intramuscular, intravenous), subarachnoid, topical, inhalation and the like can be used. Suitable dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patched absorbents (patches) and the like. Agents prepared from the compounds described herein can be administered by any suitable method capable of introducing these compounds into the bloodstream. The formulations of preferred embodiments may contain a pharmaceutically acceptable carrier or diluent known to those skilled in the art, along with a mixture of active compounds.

  The present method of treating emotional instability involves the use of dextromethorphan in combination with quinidine as an adjuvant by using known therapeutic agents such as fluoxetine hydrochloride marketed as PROZAC® by Eli Lilly. Can be raised to a degree. Preferred adjuvants include pharmaceutical compositions conventionally used in the treatment of sick people as described herein.

  The pharmaceutical composition of the invention comprises both dextromethorphan and quinidine, or a pharmaceutically acceptable salt of dextromethorphan and / or quinidine as an active ingredient, a pharmaceutically acceptable carrier, and optionally other treatments Ingredients may also be included.

The term “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base. Suitable pharmaceutically acceptable salts include metal salts such as aluminum salts, zinc salts, alkali metal salts such as lithium, sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts; organic Salts, such as lysine salts, N, N′-dibenzylethylenediamine salts, chloroprocaine salts, choline salts, diethanolamine salts, ethylenediamine salts, meglumine (N-methylglucamine) salts, procaine salts, and tris salts; free acid salts And salts of free bases; inorganic salts such as sulfates, hydrochlorides, and hydrobromides; and information commonly used in pharmaceuticals today and well known to those skilled in the art, such as “The Merck Index” Other salts mentioned in the source are included. Any suitable ingredient may be selected to produce the active drug salt discussed herein, provided that the ingredient is non-toxic and does not substantially interfere with the desired activity. In addition to salts, pharmaceutically acceptable precursors and derivatives of these compounds can be used. Pharmaceutically acceptable dextromethorphan and / or amides of quinidine, lower alkyl esters, and protected derivatives may also be suitable for use in the preferred embodiment compositions and methods. In a particularly preferred embodiment, dextromethorphan is administered in the form of dextromethorphan hydrobromide and quinidine is administered in the form of quinidine sulfate. For example, 30 mg of dextromethorphan hydrobromide (molecular formula C ₁₈ H ₂₅ NO · HBr · H ₂ O) and 30 mg of quinidine sulfate (molecular formula (C ₂₀ H ₂₄ N ₂ O ₂ ) ₂ · H ₂ SO ₄ · 2H ₂ O) can be administered (corresponding to an effective dose of about 22 mg dextromethorphan and 25 mg quinidine). Other preferred dosages include, for example, 45 mg dextromethorphan hydrobromide and 30 mg quinidine sulfate (corresponding to an effective dosage of about 33 mg dextromethorphan and about 25 mg quinidine); 60 mg hydrobromic acid Dextromethorphan and 30 mg quinidine sulfate (corresponding to an effective dose of about 44 mg dextromethorphan and about 25 mg quinidine); 45 mg dextromethorphan hydrobromide and 45 mg quinidine sulfate (about 33 mg dextromethorphan and 37.5 mg quinidine effective dose); 60 mg dextromethorphan hydrobromide and 60 mg quinidine sulfate (corresponding to an effective dose of about 44 mg dextromethorphan and 50 mg quinidine).

  The composition can be prepared in any desired form, such as tablets, powders, capsules, suspensions, solutions, elixirs, and aerosols. For oral solid preparations, carriers such as starch, saccharides and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like can be used. In general, oral solid preparations (powder, capsules, tablets, etc.) are preferred over oral liquid preparations. However, in certain embodiments, oral liquid formulations may be preferred over oral solid formulations. The most preferred oral solid formulation is a tablet. If desired, tablets may be coated by standard wet techniques or non-technique techniques.

  In addition to the general dosage forms described above, sustained release, delayed release or controlled release compositions and / or delivery devices such as US Pat. Nos. 3,845,770, 3,916,899 No. 3,536,809, 3,598,123, and 4,008,719, and the like.

  Pharmaceutical compositions suitable for oral administration are as discrete units, such as capsules, cachets, tablets, aerosol sprays, each containing a predetermined amount of the active ingredient, or as powders or granules, or aqueous, non-aqueous liquids, It can be provided as an oil-in-water emulsion or a solution or suspension of a water-in-oil liquid emulsion. While such compositions can be prepared by any of the conventional dispensing methods, the majority of methods generally involve combining the active ingredient with a carrier that is one or more ingredients. . In general, the compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers, finely divided solid carriers or both, and then optionally shaping the product into the desired shape. .

  For example, a tablet can be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets are prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. can do. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Each tablet preferably contains from about 30 mg to about 60 mg dextromethorphan and from about 30 mg to about 45 mg quinidine, and each capsule comprises from about 30 mg to about 60 mg dextromethorphan and from about 30 mg to about 45 mg. It preferably contains 45 mg of quinidine. Most preferably, the tablets or capsules are provided in a dosage range such that the dosage can be divided and administered. For example, about 10 mg dextromethorphan and about 5 mg, 10 mg, or 15 mg quinidine; about 20 mg dextromethorphan and about 10 mg, 20 mg, or 30 mg quinidine; about 30 mg dextromethorphan and about 15 mg, 30 mg, or 45 mg A tablet, cachet, or capsule containing quinidine or the like can be provided. The dosage appropriate for the patient, the disease to be treated, and the number of doses administered per day can thus be selected conventionally. While it is generally preferred that both dextromethorphan and quinidine be included in a single tablet or other dosage form, in some embodiments it is desirable to provide dextromethorphan and quinidine in separate dosage forms. Sometimes.

  Patients suffering from emotional instability and other illnesses described herein are significantly more than dextromethorphan and the minimum amount previously considered necessary to obtain a significant therapeutic effect. It was unexpectedly found that it can be treated with a small amount of quinidine in combination. As used herein, “minimal effective therapeutic amount” refers to an adverse event that does not cause an adverse effect or that is of an acceptable degree and nature, while sufficiently preventing rapid removal of dextromethorphan from the body. Amount. More specifically, a preferred effective therapeutic amount is about 20 mg, 25 mg, or 30 mg to about 60 mg of dextromethorphan and less than about 50 mg of quinidine per day, preferably about 20 mg or 30 mg to about 60 mg of dextrose per day. Lometorphan and about 30 mg to about 45 mg of quinidine, preferably in divided doses based on the plasma half-life of dextromethorphan. For example, in a preferred embodiment, the preferred maximum specific dosage of dextromethorphan and quinidine is based on body weight, and dextromethorphan and quinidine are administered in specific mg increments to produce a specific level of μg / mL plasma. Achieving the target concentration of dextromethorphan. And it is preferable to administer a target dose every 12 hours. Minimizing the level of quinidine minimizes or eliminates the side effects observed with high doses of quinidine, and significant benefits include dextromethorphan combined with higher concentrations of quinidine Over composition.

  The combination of dextromethorphan and quinidine in a preferred embodiment can also be very effective in formulations for the treatment of other chronic diseases that do not respond well enough to other treatments. When used in combination with quinidine, dextromethorphan can effectively treat severe or refractory cough that does not respond well to non-addictive non-steroidal drugs with minimal side effects. it can. Refractory cough is the result of respiratory infections, asthma, emphysema, and other diseases that affect the lung system.

  The combination of dextromethorphan and quinidine as in a preferred embodiment can also be used in pharmaceutical compositions for the treatment of dermatitis. As used herein, “dermatitis” or “eczema” is a skin condition characterized by visible skin lesions and / or itching or burning. The combination of dextromethorphan and quinidine, as in a preferred embodiment, is also used in pharmaceutical compositions for the treatment of chronic pain from diseases such as stroke, trauma, and cancer, and neuropathic pain such as herpes zoster infection and diabetes. Can be used. Other diseases that can be treated in combination with dextromethorphan and quinidine according to preferred embodiments include sexual dysfunctions such as persistent erectile dysfunction and premature ejaculation, and tinnitus.

  The following paragraphs report the results of clinical studies. Unless otherwise indicated, dextromethorphan is administered as dextromethorphan hydrobromide in the monohydrate form (US Pharmacopoeia dextromethorphan hydrobromide), and quinidine is in the dihydrate form. It was administered as quinidine sulfate (US Pharmacopoeia quinidine sulfate).

Clinical study # 1
A clinical trial was conducted to determine the minimum dose of quinidine that inhibits the conversion of dextromethorphan to dextrorphan, and the occurrence of side effects during dextromethorphan / quinidine administration was recorded.

  A test protocol specification and detailed schedule and schedule were prepared to ensure that the protocol was consistently performed during the study.

  We conducted a phenotypic survey of dextromethorphans. This study was an open-label, single-dose study. Subjects were selected to ensure they met recruitment and non-recruitment criteria. Subjects were given a single oral dose of 30 mg capsules of dextromethorphan hydrobromide with 240 mL of tap water. A total of 58 subjects were examined and 50 subjects were dosed. In this study, each subject's ability to metabolize dextromethorphan was determined. Subjects who met the recruitment / non-recruitment criteria were left at home while taking medication. Each subject received one capsule of 30 mg dextromethorphan (PM). Urine was collected from before taking to 12 hours after taking, and dextromethorphan and dextrorphan were analyzed. Blood samples (5 mL) were taken before dosing and 2, 4, and 8 hours after dosing for plasma dextromethorphan, dextrorphan, and quinidine analysis. After a washout period of at least 2 days (drug holiday), 48 subjects who were determined to be high dextromethorphan metabolizers were asked to participate in the quinidine taking trial. Of these subjects, 46 were determined to be highly dextromethorphan metabolizers. One side effect was reported during the trial (headache classified as mild, resolved without intervention).

  A quinidine dose determination study was then performed. This study was an open-label, randomized multiple dose study. Subjects who were confirmed to be highly metabolizers were administered one dose on the evening of the first day, the next 6 days were administered at 12-hour intervals, and the final dose was administered on the morning of the eighth day. All subjects were instructed to take their own formulated medications at home at eight specific times. The subject continued to write a diary during the study to record adverse effects.

  Subjects who were randomly treated A received orally 14 times 30 mg capsules of dextromethorphan hydrobromide with 240 mL of tap water. Subjects randomized as Treatment B were orally dosed 14 times with dextromethorphan hydrobromide 30 mg / quinidine 2.5 mg capsules along with 240 mL of tap water. Subjects who were randomized to treatment C were orally dosed with dextromethorphan hydrobromide 30 mg / quinidine 10 mg capsules with 240 mL of tap water 14 times. Subjects who were randomly treated D received orally 14 doses of dextromethorphan hydrobromide 30 mg / quinidine 25 mg capsules along with 240 mL of tap water. Subjects who were randomly treated E received 14 doses of dextromethorphan hydrobromide 30 mg / quinidine 50 mg capsules along with 240 mL of tap water. Subjects who were randomized to treatment F were orally dosed with dextromethorphan hydrobromide 30 mg / quinidine 75 mg capsules with 240 mL of tap water 14 times.

  Except for one, all subjects who participated in the study met the inclusion / non-recruitment criteria indicated in the protocol. Prior to enrolling subjects in the study, the medical history, clinical laboratory assessment, and physical examination performed were reviewed. Subjects were instructed not to take grapefruit products while participating in the study. Over-the-counter drugs were banned for 3 days before taking and during the study, and prescription drugs (excluding oral contraceptives) were banned for 14 days before taking and for the study.

  A total of 46 subjects, 22 men and 24 women, participated in the study, and 45 subjects, 22 men and 23 women, completed the study. Subjects were reviewed within 21 days prior to participating in the study. Review procedures include medical history, physical examination (height, weight, physique size, vital signs, and ECG (electrocardiogram)) and laboratory tests (hematology, serum chemistry, urinalysis, HIV antibody screening, serum pregnancy, THECA ( Screening).

  Subjects were in the clinic at Day 1 (PM), Day 2 (AM), Day 3 (PM), Day 4 (AM), and Day 7 Taken on the eyes (PM) schedule. The subject reported morning dosing to the clinic on the 8th day and stayed at home for 8 hours after taking. Subjects were Day 2 (PM), Day 3 (AM), Day 4 (PM), Day 5 (AM and PM), Day 6 Eyes (AM and PM), self-medication at home on day 7 (AM). Subjects took twice a day except that they took only one dose on day 1 PM and day 8 AM.

  At the end of the study, clinical laboratory evaluations (hematology, chemistry, urinalysis), vital signs, ECG, and a simple physical examination were performed. Subjects were instructed to inform the study physician and / or maintenance nurse of any adverse events that occurred during the study.

  On day 8, blood samples (5 mL) were taken before dosing and at 2, 4, and 8 hours after dosing for dextromethorphan, dextrorphan, and quinidine analysis. A total of 8 blood samples (40 mL) were taken during the study (including dextromethorphan screening) for drug analysis. Plasma samples were separated by centrifugation, then frozen at −20 ° C. and kept frozen until examined. Urine was collected up to 12 hours after the first, fifth and thirteenth doses from before taking. Urine samples were pooled throughout collection. At the end of the collection period, the total volume was recorded and two aliquots (partial samples) were frozen at -20 ° C until analyzed for dextromethorphan and dextrorphan.

  A total of 46 subjects took the dose, and 45 subjects completed the study. One subject discontinued / declined the study because he could not tolerate the adverse events experienced. The average age of the subject is 51 years (range 20 to 86 years), the average height of the subject is 67.6 inches (range 61.5 to 74.5 inches), and the average weight of the subject is 162 .9 pounds (range 101.0 pounds to 229.0 pounds).

  A total of 8 subjects were placed in treatment groups B, D, and E. Seven subjects were placed in treatment groups A and C.

  Thirty-four (74%) subjects experienced a total of 150 adverse events. Except for one serious adverse effect, all adverse events were classified as mild (96%) or normal (4%). The most commonly reported adverse events include headache, loose stool, dizziness on standing, dizziness, and nausea (nausea). Relationship to study drug was classified as 120 out of 150 adverse events (80%) might be related, likely related, or almost certainly related. There was no clear difference in the type or frequency of adverse events observed between groups taking. There were no clinically significant trends with regard to vital signs, physical examinations, or laboratory tests.

Clinical study # 2
The purpose of this study was to determine the pharmacokinetic parameters of dextromethorphan for single and multiple doses of capsule formulations containing 30 mg dextromethorphan hydrobromide and 25 mg quinidine sulfate, To determine the difference between these pharmacokinetic parameters between low-metabolites and low-metabolites, and to record the occurrence of side effects during drug administration. This study is intended for open-label single and multiple doses.

  Ten subjects participated in the study. A total of 9 subjects completed the study. Ten subjects were included in the safety analysis and nine were included in the pharmacokinetic analysis. All subjects who participated in this study were judged healthy volunteers by the investigators.

  The test formulation was a capsule of 30 mg dextromethorphan hydrobromide and 25 mg quinidine sulfate. All subjects were orally dosed with a capsule of 30 mg dextromethorphan hydrobromide and 25 mg quinidine sulfate with a total of 15 doses every 12 hours along with 240 mL of water.

  From the plasma concentration-time data of dextromethorphan, dextrorphan, and quinidine at day 1, day 4, and day 8, the non-compartmental pharmacokinetic parameters Cmax, Tmax, and AUC (0-12) were calculated. Calculated. In addition, the parameters Kel and T1 / 2el were calculated for dextrorphan (day 8) and quinidine (day 1, day 4, and day 8).

  The amount of dextromethorphan and dextrorphan excreted in the urine from the collected urine at 12:00 on the first day (after the first dose), the eighth day (after the 15th dose), and the 9th to the 14th days Calculated. For each day of urine collection, the molar metabolic ratio (dextromethorphan: dextrorphan) was calculated.

  Subjects were evaluated by physical examination, vital signs, electrocardiogram (ECG), laboratory tests (hematology, serum chemistry, and urinalysis), and adverse event assessment.

  Descriptive statistics including the mean, median, standard deviation, coefficient of variation, N, minimum, and maximum for each parameter were calculated daily for all subjects. In addition, descriptive statistics were shown for each subgroup: high metabolizer (EM) and low metabolite (PM).

  The normal linear model (GLM), which is a normal theory, is transformed into Cmax and AUC (0 to 12) log conversion parameters and non-transformed Tmax (dextromethorphan and dextrorphan) and Cmax, AUC (0 to 0) non-conversion parameters. 12), and Tmax (quinidine). The ANOVA model included the factor group (EM or PM), the number of subjects in the group, the number of days, and the number of days of interaction per group. Subjects within the group mean square were used to test group effects, and residuals (error mean square) were used to test all other main effects. Furthermore, the assumptions of 1 day = 4 days, 1 day = 8 days, and 4 days = 8 days were verified.

Safety and tolerability were evaluated by data listing and calculation of summary statistics as follows. That is, hematology, serum chemistry, and urinalysis test results before and after administration were listed in the data list for each subject. Descriptive statistics were reported at each collection point, the changes from pre-dose to post-dose were summarized and statistically tested using a paired paired t-test (H ₀ : change = 0). A fluctuation table showing fluctuations outside the range from before administration to after administration was prepared. Out-of-normal range and clinically significant laboratory values were listed for each subject.

For vital signs measurements, ie systolic and diastolic blood pressure, pulse rate, respiration, and body temperature, descriptive statistics (mean, standard deviation, minimum, maximum, and sample size) are given as time points (screening and 8 days after taking). Summary statistics are shown for each metabolite type. Differences between screening measurements and post-dose measurements were shown and statistically tested using paired t-test (H ₀ : difference = 0). The results of individual vital signs are listed in the data list for each subject. We also confirmed changes in physical examination results that occurred before and after taking.

A 12-lead ECG was recorded before taking. Descriptive statistics (mean, standard deviation, minimum, maximum, and sample size) for ECG measurements, ie QRS, PR, QTc, and heart rate, by time point (before and 8 days after taking) Reported to. Summary statistics are shown for each metabolite type. The difference between the measured value before taking and the 8th day after taking was shown and statistically tested using a paired t-test (H ₀ : difference = 0). ECG results are listed in the data list for each subject.

  Adverse events were classified using the COSTART Dictionary 5th edition. The list includes the number of subjects reporting adverse events for each metabolite type as a percentage of the number of subjects taken. The list also shows the frequency, severity, and relationship to study drug of adverse events. Adverse events were listed by subject, including the reporter's language, severity, frequency, and relationship to treatment.

  The average pharmacokinetic parameters of dextromethorphan, dextrorphan, and quinidine are summarized in Table 1 for dextromethorphan high metabolite (EM), dextromethorphan low metabolite (PM), and all subjects.

デキストロメトルファンの高代謝者（ＥＭ）、デキストロメトルファンの低代謝者（ＰＭ）、および全被験者について、平均尿中代謝比（デキストロメトルファン：デキストロルファン）を表２にまとめて示す。

Table 2 summarizes the average urinary metabolic ratio (dextromethorphan: dextrorphan) for dextromethorphan high metabolizers (EM), dextromethorphan low metabolizers (PM), and all subjects.

この試験の間、重大な有害事象は起こらなかった。薬物に関係のある有害事象には、無力症、下痢、食欲不振、悪心、嘔吐、不安、離人症、不眠症、および傾眠を含めた。有害事象の大多数は、重症度が軽く、すべてが治療なしで解消した。服用後の高代謝者のグループではＱＴ間隔の延長および心拍数の低下が認められた。バイタルサイン、身体検査、またはごく普通の臨床検査試験に関しては、臨床上重要な傾向が認められなかった。

There were no serious adverse events during this study. Drug-related adverse events included asthenia, diarrhea, anorexia, nausea, vomiting, anxiety, divorce, insomnia, and somnolence. The majority of adverse events were mild in severity and all resolved without treatment. In the group of hypermetabolists after taking the drug, prolongation of QT interval and decrease in heart rate were observed. There were no clinically significant trends with regard to vital signs, physical examination, or common laboratory tests.

  During this study, small doses of quinidine suppressed dextromethorphan metabolism and increased systemic availability. This effect was most noticeable among highly metabolized people. The mean urinary metabolic ratio (dextromethorphan: dextrorphan) increased at least 29-fold by day 8 in highly metabolized people. Plasma dextrorphan AUC (0-12) increased approximately 8-fold between day 1 and 8, whereas mean plasma dextrorphan AUC (0-12) increased between days 1 and 8. Remained the same between days.

  The effect of quinidine on dextromethorphan metabolism in hypometabolites was not clear. The urinary metabolic ratio did not appear to change with quinidine treatment. Both dextromethorphan and dextrorfan emissions increased. However, dextrorphan fan emissions increased in proportion to dextromethorphan. This suggests that in low metabolizers, quinidine did not inhibit the metabolism of dextromethorphan to dextrorphan. However, dextromethorphan AUC (0-12) increased 6.1-fold from day 1 to 8, whereas dextrorphan AUC (0-12) increased 4.8-fold, This is consistent with a slight decrease in metabolic clearance.

  The pharmacokinetics of quinidine was similar between high and low metabolizers. The average quinidine elimination half-life (6.78-8.14 hours) was similar to previously reported values.

  Administration of dextromethorphan hydrobromide and quinidine sulfate capsules as single-dose or multi-dose products appeared to be well tolerated in this healthy population.

Clinical study # 3
The purpose of this study was to minimize the dose of quinidine sulfate that effectively inhibits the conversion of 45 mg dextromethorphan to dextrorphan, and to minimize the amount of quinidine that effectively inhibits the conversion of 60 mg dextromethorphan to dextrorphan. Determining the dose and recording the occurrence of side effects during administration of dextromethorphan in combination with quinidine.

  This medication interaction study was a Phase 1, open-label, parallel group, multiple dose, single center safety and pharmacokinetic study. A total of 64 subjects were scheduled, but 65 subjects participated in the study. A total of 47 subjects completed the study and were included in the pharmacokinetic analysis. All subjects were included in the safety analysis. Men and women aged 18 to 60 years who were confirmed to be highly metabolized dextromethorphan participated. All subjects were determined to be healthy volunteers. Participating subjects met the criteria for recruitment and non-recruitment.

  The test formulation was a capsule of dextromethorphan hydrobromide and quinidine sulfate, administered orally with water. From day 1 to day 8, subjects who received treatment A were orally dosed once a day with capsules of 60 mg of dextromethorphan hydrobromide / 0 mg of quinidine sulfate along with 240 mL of water. From day 1 to day 8, subjects who received treatment B were orally dosed once a capsule with 60 mL of dextromethorphan hydrobromide / 30 mg of quinidine sulfate along with 240 mL of water. From day 1 to day 8, subjects receiving treatment C were orally dosed once a day with capsules of 60 mg dextromethorphan hydrobromide / 45 mg quinidine sulfate along with 240 mL of water. From day 1 to day 8, subjects who received treatment D were orally dosed once a capsule with 60 mL of dextromethorphan hydrobromide / 60 mg of quinidine sulfate together with 240 mL of water. From day 1 to day 8, subjects who received treatment E were orally dosed once daily with 1 capsule of 45 mg dextromethorphan hydrobromide / 0 mg quinidine sulfate along with 240 mL of water. From Day 1 to Day 8, subjects receiving Treatment F were orally dosed once daily with 1 capsule of 45 mg dextromethorphan hydrobromide / 30 mg quinidine sulfate along with 240 mL of water. From day 1 to day 8, subjects who received treatment G were orally dosed once a day with capsules of 45 mg of dextromethorphan hydrobromide / 45 mg of quinidine sulfate along with 240 mL of water. From day 1 to day 8, subjects who received treatment H were orally dosed once daily with 1 capsule of 45 mg dextromethorphan hydrobromide / 60 mg quinidine sulfate along with 240 mL of water. For treatments B, C, D, F, G, and H, subjects were given one dose of dextromethorphan hydrobromide at the first time (60 mg for treatments B, C, and D, or treatments F, G, and H 45 mg) was taken without quinidine, followed by the 14 capsules shown. That is, all subjects received treatment A or E once as a baseline.

  The first dose of Treatments A and E was considered as a reference. Phenotypic determination was performed using 30 mg capsules of dextromethorphan hydrobromide. The subject was orally dosed once with 30 mL capsules of dextromethorphan hydrobromide with 240 mL of water.

  Non-compartmental analysis was used to calculate plasma pharmacokinetic parameters Cmax, Tmax, AUC (0-5), and AUC (0-12). The pharmacokinetic parameters were summarized and descriptive statistics for all groups were calculated. The changes from baseline for these parameters were calculated and summarized. The urinary metabolic ratio (dextromethorphan / dextrorphan) was calculated. Descriptive statistics were calculated for all groups, and changes in metabolic ratio from baseline were calculated and summarized.

  Adverse event assessment, hematology, blood chemistry, urinalysis monitoring, vital signs and electrocardiogram (ECG) measurements, and physical examinations were performed to assess safety.

  After multiple doses of dextromethorphan and quinidine, continuous plasma dextromethorphan and dextrorphan concentrations on days 1 and 8, quinidine concentration on day 8, and days 1, 3 The amount of dextromethorphan and dextrorphan excreted in the urine from the 12:00 urine collection on day 1 and day 7 was measured to assess the effect of quinidine on the pharmacokinetics of dextromethorphan. From the plasma concentration-time data of dextromethorphan and dextrorphan at day 1 and 8 and quinidine at day 8, the non-compartmental pharmacokinetic parameters Cmax, Tmax, AUC (0-5), and AUC ( 0-12) were calculated. The amount of dextromethorphan and dextrorphan excreted in the urine was calculated from 12:00 collected urine on day 1, day 3, and day 7. For each day of urine collection, the molar metabolic ratio (dextromethorphan: dextrorphan) was calculated. To evaluate the effect of quinidine on dextromethorphan, SAS PROC Mixed was used for four dextromethorphan and dextromethorphan parameters AUC obtained from quinidine treatment with dextromethorphan dosages of 60 mg and 45 mg, respectively. Analysis of variance. In addition to the least mean square of each dose, the difference between doses (a pair of comparisons), the P value for the significance of the difference is shown. In order to evaluate the influence of dextromethorphan on quinidine, analysis of variance was performed on the parameter AUC of quinidine using SAS PROC Mixed. In addition to the least mean square of each dose, the difference between doses (a pair of comparisons), the P value for the significance of the difference is shown.

  Safety and tolerability were evaluated by calculating summary statistics and presented in a data listing for each subject. Adverse events were encoded using MedDRA Adverse Event Dictionary (version 3.0, 2000). The frequency, type, severity, and relationship to study drug of adverse events caused by treatment were shown, and comparisons were made between treatments.

  In clinical trials, screening tests and post-test measurements, along with changes between both time points, along with descriptive statistics for serum and hematology tests (median, mean, standard deviation, minimum, maximum, and sample) Size). For serum chemistry, hematology, and urinalysis, a variation table from screening to post-test was created. Out-of-range clinical laboratory results and associated retest values were listed.

  Descriptive statistics (median, mean, standard deviation, minimum, maximum, and sample size) for baseline and post-treatment vital signs and 12-lead ECG (ECG) measurements, and changes between both time points Calculated. The ECG variation table from baseline to post dose is also shown.

  The arithmetic mean of the pharmacokinetic parameters of dextromethorphan, dextrorphan, and quinidine in plasma after treatments A, B, C, D, E, F, G, and H, and statistically for each treatment group The comparison results are shown in the following table. Table 3 summarizes the pharmacokinetic parameters of DM in plasma after taking 60 mg of dextromethorphan.

表４は、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関する血漿中デキストロメトルファンＡＵＣ（０〜１２）の統計学的な比較をまとめて示すものである。

Table 4 summarizes the statistical comparison of plasma dextromethorphan AUC (0-12) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表５は、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関する血漿中デキストロメトルファンＡＵＣ（０〜ｔ）の統計学的な比較をまとめて示すものである。

Table 5 summarizes the statistical comparison of plasma dextromethorphan AUC (0-t) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表６は、４５ｍｇのデキストロメトルファンを服用した後の血漿中のデキストロメトルファンの薬物動態パラメータをまとめて示すものである。

Table 6 summarizes the pharmacokinetic parameters of dextromethorphan in plasma after taking 45 mg of dextromethorphan.

表７は、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関する血漿中デキストロメトルファンＡＵＣ（０〜１２）の統計学的な比較をまとめて示すものである。

Table 7 summarizes the statistical comparison of plasma dextromethorphan AUC (0-12) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表８は、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関する血漿中デキストロメトルファンＡＵＣ（０〜ｔ）の統計学的な比較をまとめて示すものである。

Table 8 summarizes the statistical comparison of plasma dextromethorphan AUC (0-t) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表９は、６０ｍｇのデキストロメトルファンを服用した後の血漿中のデキストロメトルファンの薬物動態パラメータをまとめて示すものである。

Table 9 summarizes the pharmacokinetic parameters of dextromethorphan in plasma after taking 60 mg of dextromethorphan.

表１０は、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関しての血漿中デキストロメトルファンＡＵＣ（０〜１２）の統計学的な比較をまとめて示すものである。

Table 10 summarizes the statistical comparison of plasma dextromethorphan AUC (0-12) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表１１は、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関しての血漿中デキストロメトルファンＡＵＣ（０〜ｔ）の統計学的な比較をまとめて示すものである。

Table 11 summarizes the statistical comparison of plasma dextromethorphan AUC (0-t) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表１２は、４５ｍｇのデキストロメトルファンを服用した後の血漿中のデキストロメトルファンの薬物動態パラメータをまとめて示すものである。

Table 12 summarizes the pharmacokinetic parameters of dextromethorphan in plasma after taking 45 mg of dextromethorphan.

表１３は、４５ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関しての血漿中デキストロメトルファンＡＵＣ（０〜１２）の統計学的な比較をまとめて示すものである。

Table 13 summarizes the statistical comparison of plasma dextromethorphan AUC (0-12) with respect to the effect of taking quinidine versus 45 mg dextromethorphan.

表１４は、４５ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関しての血漿中デキストロメトルファンＡＵＣ（０〜ｔ）の統計学的な比較をまとめて示すものである。

Table 14 summarizes the statistical comparison of plasma dextromethorphan AUC (0-t) with respect to the effect of taking quinidine versus 45 mg dextromethorphan.

表１５は、６０ｍｇのデキストロメトルファンを服用した後の血漿中のデキストロメトルファンの薬物動態パラメータをまとめて示すものである。

Table 15 summarizes the pharmacokinetic parameters of dextromethorphan in plasma after taking 60 mg of dextromethorphan.

表１６は、４５ｍｇのデキストロメトルファンを服用した後の血漿中のデキストロメトルファンの薬物動態パラメータをまとめて示すものである。

Table 16 summarizes the pharmacokinetic parameters of dextromethorphan in plasma after taking 45 mg of dextromethorphan.

表１７は、異なるデキストロメトルファン／キニジン用量の組合せに関しての血漿中キニジンＡＵＣ（０〜１２）の統計学的な比較をまとめて示すものである。

Table 17 summarizes the statistical comparison of plasma quinidine AUC (0-12) for different dextromethorphan / quinidine dose combinations.

表１８は、異なるデキストロメトルファン／キニジン用量の組合せに関しての血漿中キニジンＡＵＣ（０〜ｔ）の統計学的な比較をまとめて示すものである。

Table 18 summarizes the statistical comparison of plasma quinidine AUC (0-t) for different dextromethorphan / quinidine dose combinations.

表１９には、６０ｍｇのデキストロメトルファンを服用した後の尿の薬物動態パラメータについての代謝比をまとめて示す。

Table 19 summarizes the metabolic ratios for urine pharmacokinetic parameters after taking 60 mg of dextromethorphan.

表２０には、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関して、Ａｅ（１５６〜１６８時間）についての尿中代謝比の統計学的な比較をまとめて示す。

Table 20 summarizes the statistical comparison of urinary metabolic ratios for Ae (156-168 hours) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表２１には、６０ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関して、ＣｕｍＡｅ（１５６〜１６８時間）についての尿中代謝比の統計学的な比較をまとめて示す。

Table 21 summarizes the statistical comparison of urinary metabolic ratios for CumAe (156-168 hours) with respect to the effect of taking quinidine versus 60 mg dextromethorphan.

表２２には、４５ｍｇのデキストロメトルファンを服用した後の尿の薬物動態パラメータについての代謝比をまとめて示す。

Table 22 summarizes the metabolic ratios for urine pharmacokinetic parameters after taking 45 mg of dextromethorphan.

表２３には、４５ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関して、Ａｅ（１５６〜１６８時間）についての尿中代謝比の統計学的な比較をまとめて示す。

Table 23 summarizes the statistical comparison of urinary metabolic ratios for Ae (156-168 hours) with respect to the effect of taking quinidine versus 45 mg dextromethorphan.

表２４には、４５ｍｇのデキストロメトルファンの服用に対するキニジン服用の効果に関して、ＣｕｍＡｅ（１５６〜１６８時間）についての尿中代謝比の統計学的な比較をまとめて示す。

Table 24 summarizes the statistical comparison of urinary metabolic ratios for CumAe (156-168 hours) with respect to the effect of taking quinidine versus 45 mg dextromethorphan.

データは、デキストロメトルファンと硫酸キニジンの同時投与が安全であり、最高の用量レベル（デキストロメトルファン６０ｍｇ／キニジン６０ｍｇ）まで耐容性が中程度に良いことを示唆している。

The data suggests that co-administration of dextromethorphan and quinidine sulfate is safe and moderately tolerated up to the highest dose level (dextromethorphan 60 mg / quinidine 60 mg).

  During the study, 48 (74%) of the 65 subjects taken had experienced a total of 279 adverse events caused by treatment. After the 60 mg dextromethorphan treatment, 27 (84%) of the 32 subjects who took the dose reported 206 adverse events, and after the 45 mg dextromethorphan treatment, the 33 subjects who took the dose Of these, 21 (64%) reported 73 adverse events. Twelve subjects after 60 mg dextromethorphan treatment and 5 subjects after 45 mg dextromethorphan treatment discontinued the study due to adverse events.

  Vertigo, nausea, and headache were the most common adverse events that occurred in both dextromethorphan groups, with fewer reports of adverse events following 45 mg dextromethorphan treatment. All adverse events were mild or normal and no serious adverse events occurred. There were no clinically significant differences between treatment groups in terms of laboratory test results, vital signs, physical examination, or ECG results.

  During this study, quinidine suppressed the metabolism of dextromethorphan taken at 45 mg and 60 mg, increasing the systemic availability of dextromethorphan. The dose of 60 mg quinidine resulted in the greatest dextromethorphan AUC for both 45 mg and 60 mg dextromethorphan doses compared to 30 mg and 45 mg quinidine doses. However, statistical comparisons showed not only that there were statistically significant differences in quinidine inhibition of dextromethorphan metabolism between different quinidine doses. Based on a statistical comparison of dextromethorphan AUC, the lowest effective dose of quinidine that inhibits metabolism of 45 and 60 mg dextromethorphan is 30 mg. Therefore, a dose of 30 mg quinidine is recommended for dextromethorphan suppression.

  The occurrence of side effects upon co-administration of dextromethorphan and quinidine sulfate indicated that the treatment was moderately well tolerated up to the highest dose level (dextromethorphan 60 mg / quinidine 60 mg).

Clinical study # 4
The purpose of this study was to determine the efficacy of taking a 30DM / 30Q combination twice daily in a population of ALS subjects with pseudobulbar affect, compared to an individual dose of 30 mg DM and 30 mg Q, It was to evaluate safety and tolerability.

  This was a multicenter, randomized, double-blind, controlled, parallel group study. All study drugs were self-administered orally every 12 hours for 28 days. The study included a screening visit and three other visits on days 1, 15, and 29. The 29th day was the last day for the subject to be involved in the test, and it was possible to stay anywhere from the morning of the 26th to the morning of the 32nd.

  Subjects who were clinically diagnosed with pseudobulbar affect were generally examined for health within 4 weeks prior to entering the study. All eligible subjects earned a score of 13 or more Center for Neurological Study-Lability Scale (CNS-LS) at the first day visit.

  Subjects were randomly assigned to one of three treatment groups to receive 30 DM / 30Q, or 30 mg DM, or 30 mg Q. Subjects were given a diary to record the date and time each dose was taken, the number of episodes of laughing / crying, and the adverse events that occurred since the last visit. Diary cards were collected on day 15 and at the end of the test.

  During the treatment period, subjects were asked to fill out a CNS-LS questionnaire and visual analog scale every two weeks (Day 1, Day 15, and Day 29) to improve quality of life (QOL) and quality of interpersonal relationships. (QOR) was evaluated. At the screening visit and on day 29, clinical psychologists or other approved clinicians performed the Hamilton Depression Rating Scale (HRSD). On days 15 and 29, safety was assessed by reviewing adverse events, physical examination results, vital signs, laboratory values, and the resulting electrocardiogram (ECG). In addition to blood samples collected to obtain laboratory data, blood was also collected for pharmacokinetic analysis and CYP2D6 genotyping. Each subject had a diary that daily recorded the number of episodes experienced, medications taken, and all adverse events.

  DM and Q were selected as control groups because they are components of the drug being investigated in this study (30DM / 30Q).

  Subjects included in this study were between 18 and 80 years of age (including 18 and 80 years). The subject had a confirmed diagnosis of ALS or first positively ALS according to World Neurological Association (WFN) criteria and had a history of pseudobulbar affect. Every effort was made to keep the subject enrolled in the study, but if the subject decided to decline, every effort was made to complete all assessments described on day 29 of Table 25. did. Subject was informed of why he declined the study. Subjects who declined to study were not allowed to rejoin the study, and randomized subjects were not replaced.

  Study medication was randomly assigned to 4 blocks. Each block randomly included two assignments for 30DM / 30Q, an assignment for DM, and an assignment for Q. Specifically, each block was constructed by selecting one of the four that could be given first. One of the remaining three treatments was selected and then given and this was repeated. Subject numbers were assigned to test locations in one block of four assignments at a time.

  There were three treatments administered in this study: 30DM / 30Q, 30 mg DM, or 30 mg Q. The study drug was given as a hard gelatin capsule. The contents of the capsule are listed in Table 25. All drugs used in this study were prepared according to current pharmaceutical manufacturing and quality control standards (cGMP).

被験者は、２８日間、１日２回（１２時間ごと）１カプセルを服用した。最初の一服を１日目の晩に服用し、最後の一服を２９日目の朝に服用した。調査員によって、同一のブリスターパックに入った３０ＤＭ／３０Ｑのカプセル、ＤＭのカプセル、およびＱのカプセルが与えられたが、カプセルはすべて、外観および重量が同一であった。

Subjects took 1 capsule twice daily (every 12 hours) for 28 days. The first dose was taken on the evening of the first day and the last dose was taken on the morning of the 29th day. The investigators gave 30DM / 30Q capsules, DM capsules, and Q capsules in the same blister pack, all capsules having the same appearance and weight.

  The subject had decided not to take the forbidden drugs during the study or for a week before the start of taking the first day. These drugs include amantadine, amitriptyline, all antidepressants including St. John's wort, all monoamine oxidase inhibitors, aspirin (acetaminophen recommended for pain or fever), captopril, cimetidine, desipramine, Dextromethorphan (generic cough medicine), digoxin, diltiazem, erythromycin, fluoxetine, imipramine, itraconazole, ketoconazole, nortriptyline, paroxetine, quinidine, quinine, and verapamil. At each visit, the subject was asked if they had taken any medication and if so, the medication was recorded on the case record form.

  Subjects were instructed to bring unused study medication at the 15th visit and to return all unused study medication to the clinic at the end of study participation. The total number of minutes taken was divided by the total number of minutes planned and the result multiplied by 100 to calculate the percent taken. Subjects were considered compliant if they were taking 80% of the prescribed dose.

  The primary efficacy variable was the CNS-LS score. All efficacy variables related to the change were determined by subtracting the baseline score from the mean of non-missing scores on day 15 and day 29. Secondary efficacy variables were laughing / crying episodes, QOL score, and QOR score. All efficacy variables related to the change were determined by subtracting the baseline score from the average of the 15 and 29 day scores.

  The CNS-LS questionnaire used to assess primary efficacy is a seven-item self-reported scale that gives a score for total pseudobulbar affect and takes about 5 minutes for the subject to complete. The range of possible scores is 7-35. Since it has been reported in the literature to provide the highest incremental validity accurately predicting a neurologist's diagnosis with a sensitivity of 0.84 and specificity of 0.81 for 82% of the participants, 13 A cut-off score was selected. This question is the only measure of pseudobulbar affect that has been confirmed to be used in ALS subjects.

  Secondary efficacy was assessed using two 10 cm visual analog scales (VAS). One scale asks subjects how much they thought that uncontrollable laughter, tearfulness, or anger had an impact on their overall quality of life during the last week, and the other scale asked subjects for last week. Inside, they asked how much they thought that uncontrollable laughter, tears, or anger influenced the quality of their relationship with others. It took less than 1 minute to complete each scale. Subjects recorded daily symptoms of morbid laughter and crying in the diary.

  Safety was assessed by the following measurements: adverse events, laboratory values, vital signs, physical examination, and resting ECG. Adverse events, whether considered to be related to treatment or not, from adverse medical events, including interventional diseases that occur during the course of the clinical trial after initiation of treatment, or from the subject's baseline (pre-treatment) status Defined as all unintended changes. An adverse event is any inconvenient, unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of the drug, whether or not considered related to the drug. It was. Clinically, changes associated with normal growth and development that do not deviate from the frequency or degree normally expected are not adverse events (eg, the onset of menstruation at a physiologically relevant time). Clinical adverse events were described by diagnosis rather than by symptom when possible (eg, colds or seasonal allergies rather than “nasal noses”).

  The severity of adverse events was graded on a three-point scale and reported in detail as indicated on the case record form. Mild—Easily tolerated, causes minimal discomfort and does not interfere with normal daily activities; moderate—discomforts enough to interfere with normal daily activities; and severe—normal daily activities Disable and / or prevent activity The investigator determined the relationship between the study drug and each adverse event using the following definitions: Not related-the event was clearly related to other factors such as the subject's clinical status, therapeutic intervention, concurrent medications administered to the subject; unlikely- The event was most likely caused by other factors, such as the subject's clinical condition, therapeutic intervention, concurrent medication administered to the subject, and did not follow a known pattern of response to the study drug; Not possible-the event was in accordance with a reasonable time sequence from the time of drug administration and / or in accordance with a known response pattern to the study drug, but was administered to the subject's clinical condition, therapeutic intervention, subject It could also have occurred due to other factors such as concurrent drugs; probable-the event was tested according to a reasonable time sequence from the time of drug administration According to the known response pattern to the product, and could not be reasonably explained by other factors such as the subject's clinical condition, therapeutic intervention, concurrent medications administered to the subject; highly probable) —the event follows a reasonable time sequence from the time of drug administration, follows a known response pattern to the study drug, and other subjects such as the subject's clinical status, therapeutic intervention, concurrent medications administered to the subject, etc. In addition to what could not be reasonably explained by some factors, it occurs immediately after administration of the study drug, improves when the drug is stopped, or recurs after repeated exposure.

  Severe adverse events have the following consequences: death; life-threatening experiences (those that immediately put subjects at risk of death from adverse events when they occur, eg, they are occurring in a more serious form Does not include adverse events that may have caused death); persistent or serious disability / incapacity (capacity is a substantial ability of a person to perform normal living functions) All adverse events that occurred at any given dose resulting in either inpatient hospitalization or prolonged hospital stay; and congenital malformations / congenital abnormalities.

  Subjects were instructed to report any adverse events immediately. Severe adverse events include the following details: event severity, start date, stop date, intensity, frequency, relationship to study drug, treatment taken for study drug, required treatment, and outcome to that point Was evaluated. These details were recorded on a case record sheet. When it was necessary and appropriate, detailed reports including copies of hospital case reports, autopsy reports, and other documents were reported following such preliminary reports.

  Blood and urine were collected for clinical chemistry, hematology, urinalysis, and pregnancy testing at the screening visit and on day 29. In the case of abnormal laboratory values, subjects were retested within one week, and subjects were followed up until values returned to normal ranges and / or a reasonable explanation for the abnormality was found.

Systolic and diastolic blood pressure, heart rate, and respiratory rate values were obtained at the screening visit and at all other study visits. All values outside the predetermined range were tagged on the subject's data list. An electrocardiogram (12 leads) was used to obtain heart rate (VR), QT, Q- _Tc interval, pulse rate (PR), and QRS period. Blood samples (10 mL whole blood) were collected from each subject for CYP2D6 genotyping at the screening visit to determine which subjects were DM low metabolizers and high metabolizers. On day 29, blood samples were taken to determine the concentration of DM, DX, and Q in the plasma. The relationship between plasma drug concentration and change in CNS-LS score was determined and the effect of CYP2D6 genotype on this relationship was evaluated.

  The sample size of 48 subjects in the 30DM / 30Q group and 24 subjects in each of the DM group and the Q group detects a difference in CNS-LS score of 5.5 between the DM / Q group and each other group It was enough to do. These calculations were made based on standard deviations of 7, 5, and 3 for the DM / Q group, DM group, and Q group, respectively. The test power is 5 on both sides assuming that the baseline / day 15 and baseline / 29 day correlations are both 0.3 and the 15/29 day correlation is 0.7. Based on the% test, it is about 85%. The assumptions underlying the sample size were drawn from a small-scale crossover study of 14 subjects, in which the mean change from baseline for DM / Q subjects was -6. The average change in subjects treated with placebo was +0.83 with a standard deviation of 3.2.

  A total of 140 subjects were randomly assigned to treatment groups, with 70 as 30DM / 30Q group, 33 as DM group, and 37 as Q group. Sample size calculations required only 48 subjects in the 30DM / 30Q group and 24 subjects in each of the other treatment groups. Thus, under the assumptions made in the sample size calculation, the number of subjects in each group was sufficient to detect a clear difference in treatment effect. The percentage of subjects with medication compliance ≧ 80% was 73.5 in the 30DM / 30Q group, 87.9 in the DM group, and 86.5 in the Q group.

  In this study, three datasets, a safety data set consisting of data from 140 subjects, a treatment significance data set consisting of data from 129 subjects, and an efficacy assessment consisting of data from 101 subjects. The data set was analyzed. The definition of these three populations is as follows. Safety population—all randomized subjects; therapeutic significance population—all subjects who were not “hypometabolites” of cytochrome P450 2D6; and efficacy assessment population—ITT in compliance with the protocol All subjects in the population. The subject was deemed to have complied when he performed the 29th day visit, completed all test procedures, and took 80% of the scheduled dose.

  The demographic characteristics of the ITT population are shown in Table 26, the history of ALS is shown in Table 27, and the baseline scores for depression, pseudobulbar affect, QOL, and QOR are shown in Table 28.

どの個体群統計変数についても３０ＤＭ／３０ＱグループとＤＭグループおよびＱグループとに統計学的に有意な差はなかった。ベースラインの特徴における唯一の統計学的に有意な差は、ＱＯＬスコアにあった。３０ＤＭ／３０Ｑグループの被験者は、他の２つの治療グループのそれぞれの被験者よりも、ベースラインの自身のＱＯＬが良いと評価した。有効性評価母集団でも同様の個体群統計結果が得られ、ベースラインの特徴の傾向は、ＩＴＴ集団のものと同じ方向にあった。有効性の一次および二次分析で興味ある集団は、ＩＴＴ集団であった。したがって、本文に示した結果はすべて、この集団から得たものである。

There was no statistically significant difference between the 30DM / 30Q group and the DM and Q groups for any population statistical variable. The only statistically significant difference in baseline characteristics was in the QOL score. Subjects in the 30DM / 30Q group rated their baseline QOL better than those in each of the other two treatment groups. Similar demographic results were obtained in the efficacy assessment population, with baseline feature trends in the same direction as those in the ITT population. The population of interest in the primary and secondary analysis of efficacy was the ITT population. Therefore, all the results presented here are from this population.

  The primary efficacy analysis adjusts changes from baseline in the CNS-LS score to the institutional and baseline CNS-LS scores. Table 29 shows the descriptive statistics for the ITT population.

３つの治療グループそれぞれについて、ベースライン、１５日目、および２９日目のＣＮＳ−ＬＳスコアの分布を図１に示す。これらの分布は、ベースライン・スコアまたは試験場所に合わせて調整していない。図１に示すとおり、ＣＮＳ−ＬＳスコアの分布は対称的であり、外れ値を１点しか含まない。これらの分布から、ＣＮＳ−ＬＳスコアの分析のためにＡＮＣＯＶＡ（共分散分析）を使用することが支持される。予期してプロトコルで指定したように、施設およびベースラインのＣＮＳ−ＬＳスコアに合わせて調整したＣＮＳ−ＬＳスコアの平均改善度の差は、Ｆｒｉｓｏｎ ａｎｄ ＰｏｃｏｃｋのＡＮＣＯＶＡ法に従う線形回帰を使用して分析した。この分析の結果を表３０に示す。まったく調整しなかった、またはベースラインのＣＮＳ−ＬＳスコアについてのみ調整した追加の分析結果もこの表に示す。

The distribution of CNS-LS scores at baseline, day 15 and day 29 for each of the three treatment groups is shown in FIG. These distributions are not adjusted for baseline scores or test locations. As shown in FIG. 1, the distribution of CNS-LS scores is symmetric and includes only one outlier. These distributions support the use of ANCOVA (covariance analysis) for analysis of CNS-LS scores. Differences in mean improvement in CNS-LS scores adjusted for institutional and baseline CNS-LS scores, as expected in the protocol, were analyzed using linear regression according to Frison and Pocock's ANCOVA method did. The results of this analysis are shown in Table 30. Additional analysis results that were not adjusted at all or adjusted only for the baseline CNS-LS score are also shown in this table.

３０ＤＭ／３０Ｑで治療したグループの平均スコアは、ＤＭで治療したグループの平均スコアとＱで治療したグループの平均スコアに対して、統計学的に有意な差があった。その結果、３０ＤＭ／３０Ｑで治療した被験者は、仮性球麻痺性情動の有意な改善を示した。

The mean score of the group treated with 30DM / 30Q was statistically significant different from the mean score of the group treated with DM and the mean score of the group treated with Q. As a result, subjects treated with 30DM / 30Q showed a significant improvement in pseudobulbar affect.

  The result of the analysis specified in advance by the protocol is shown in FIG. The average reduction in CNS-LS score for the three treatment groups has been adjusted from the primary efficacy analysis of the ITT population. The reduction in CNS-LS score below the horizon was statistically significant at the indicated level of significance versus 30DM / 30Q.

  A primary efficacy analysis was also performed on the efficacy assessment and safety populations. These results are shown in Table 31. Results in these populations also showed that 30DM / 30Q significantly improved pseudobulbar affect.

これらの集団での結果も、３０ＤＭ／３０Ｑが仮性球麻痺性情動を有意に改善したことを示した。

Results in these populations also showed that 30DM / 30Q significantly improved pseudobulbar affect.

  Primary efficacy data were also adjusted for the interaction of the facility, baseline CNS-LS score, and treatment by the facility, and analyzed using linear regression according to Frison and Pocock's ANCOVA method. In some institutions, the sample size was small, so this interaction could not be evaluated.

  Analysis of secondary efficacy data was performed. The number of symptom occurrences per week was analyzed using the Poisson regression model as specified in the statistical analysis plan, and the results are shown in Table 32.

プロトコルで予め指定した、この症状の発現率の分析は、（施設に合わせて調整を行い、ポアソン回帰モデルからの症状の発現率を使用して算出した）総計の症状の発現が、ＤＭグループでは３０ＤＭ／３０Ｑグループよりも６．４倍多く、Ｑグループでは３０ＤＭ／３０Ｑグループよりも１．９倍多かったことを示した。ＤＭグループのただ１点の外れ値は、試験中に他の被験者すべての１０倍の症状の発現、すなわち、平均で１日につき１００回を上回る症状の発現を報告した被験者であった。この外れ値を除いたとき、この比率は、ＤＭグループおよびＱグループに対してそれぞれ２．３および１．８であった。どの場合も、算出されたｐ値は＜０．０００１であった。笑いおよび泣き単独の評価も、統計学的に大いに有意であった。この被験者の極端な症状の発現回数は、主として笑いの症状の発現であり、そのため、予測された泣きに対する効果は、この被験者を除いてもほとんど変わらなかった。

The analysis of the incidence of this symptom pre-designated in the protocol is the sum of the symptom occurrence (calculated using the symptom incidence from the Poisson regression model, adjusted for the facility) It was 6.4 times more than the 30DM / 30Q group and 1.9 times more in the Q group than in the 30DM / 30Q group. The only one outlier in the DM group was the subject who reported 10 times the onset of symptoms during the study, all on average more than 100 times per day. When this outlier was removed, the ratio was 2.3 and 1.8 for the DM group and Q group, respectively. In all cases, the calculated p value was <0.0001. The evaluation of laughter and cry alone was also highly significant statistically. The number of episodes of extreme symptom in this subject was mainly the symptom of laughter, and thus the predicted effect on crying was almost unchanged even when this subject was excluded.

  In assessing the number of episodes described above, there is evidence of substantial overdispersion in the data, meaning that the data did not meet the model assumptions. A number of additional analyzes were performed to assess the sensitivity of this reasoning to model specifications. These analyzes are discussed below.

  When the data was analyzed using a negative binomial model (one model for excess variance) of second order variance (mean variance), the result was that the incidence of 30DM / 30Q crying was twice that of DM (P = 0.06), 4.5 times Q (p <0.001). Corresponding factors for laughter are 2.6 (p = 0.10) and 0.9 (p = 0.84), and 2.6 (p = 0.003) and 1.5 for the whole. (P = 0.29). However, this model continues to lack data fit.

  Data were also analyzed using a negative binomial model with proportional variance (constant variance) (another model that takes into account excess variance). Results shown by residual analysis showed a better fit to this overdispersed data. The expression rates for crying estimated from this model were 2.0 (p = 0.007) and 3.3 (p <0.001) for DM and Q, respectively. For laughter, for DM and Q, the expression rates were 1.4 and 1.5, respectively, and the p values were 0.21 and 0.13. (Excluding outlier subjects, the incidence of laughter was 1.5 (p = 0.14) and 1.6 (p = 0.05).) The total number is relative to DM and Q The expression rates were 1.7 and 1.8, respectively, and the p values were 0.02 and 0.006.

  When the facility was omitted from the model as a sensitivity analysis, the degree of response was similar to the analysis including the center. The p value increased somewhat as expected. However, the normal probability plots of the residuals in these models showed that tailored adjustments substantially improved the normality of the residuals.

  Additional tests were also performed to determine the sensitivity to the resulting model assumptions. In these analyses, we examined non-parametric methods and evaluations designed to examine “stable state” differences between groups.

  Evaluation of the statistical significance of the relative effects of 30DM / 30Q, DM, and Q depends on the model assumptions used. However, statistical evaluation of relative effects consistently favored 30DM / 30Q over DM and Q, even when statistical significance was not reached in all models. These differences were statistically significant in the model in which the data for which the assumption was observed best represented.

  In order to quantify and make it easier to understand how changes in the primary efficacy variable CNS-LS score affect the number of emotional episodes, a difference of 1 point in the CNS-LS score The influence on the incidence of symptoms for 2 weeks was evaluated. Each 1 point increase in the CNS-LS score increased the mean symptom incidence by 12%. Thus, a 3.5 point decrease in the CNS-LS score would correspond to a 50% decrease in the incidence of symptoms. This is true for both the appearance of laughing symptoms and the appearance of crying symptoms. Summary statistics for QOL and QOR scores are shown in Table 33.

ベースラインおよび試験場所に合わせて調整した、３０ＤＭ／３０ＱとＤＭおよびＱとの間の、ＱＯＬおよびＱＯＲスコアの平均変化の差を表３４に示す。３０ＤＭ／３０Ｑで治療したグループは、ＤＭで治療したグループと比べて、およびＱで治療したグループと比べて、これらのスコアが統計学的に有意に向上していた。これらの結果は、全期間にわたり同様であった。

Table 34 shows the difference in mean change in QOL and QOR scores between 30DM / 30Q and DM and Q, adjusted for baseline and test location. The group treated with 30DM / 30Q had a statistically significant improvement in these scores compared to the group treated with DM and compared to the group treated with Q. These results were similar over time.

多重比較を説明するために、プロトコルで指定したように、すべての二次有効性変数を合わせ、Ｏ’Ｂｒｉｅｎの順位和法を使用して同時に分析した。多重比較に合わせて調整した後、その結果は、３０ＤＭ／３０Ｑで治療した被験者は、ＤＭ（ｐ＝０．００４１）で治療した被験者またはＱで治療した被験者（ｐ＝０．０００１）に比べて、統計学的に有意に笑いおよび泣きの症状の発現が低減し、ＱＯＬおよびＱＯＲが向上したことを示した。３０ＤＭ／３０Ｑは、ＡＬＳ患者の被験者の仮性球麻痺性情動、笑いおよび泣きの症状の発現回数、ＱＯＬ、およびＱＯＲを向上させるのに、ＤＭまたはＱのどちらよりも統計学的に有意に優れていた。

To illustrate multiple comparisons, all secondary efficacy variables were combined and analyzed simultaneously using the O'Brien rank sum method, as specified in the protocol. After adjusting for multiple comparisons, the results show that subjects treated with 30DM / 30Q compared to subjects treated with DM (p = 0.0001) or subjects treated with Q (p = 0.0001). Statistically significantly, the expression of laughing and crying symptoms was reduced, indicating that QOL and QOR were improved. 30DM / 30Q is statistically significantly superior to either DM or Q to improve pseudobulbar affect, frequency of laughter and cry episodes, QOL, and QOR in subjects with ALS. It was.

  The degree of exposure to the study drug is reported in Table 35 in terms of the number of doses of the drug. Mean exposure days were very similar in all treatment groups.

悪心は、経験された最も一般的な有害事象であり、ＤＭグループ［２名（６．１％）］またはＱグループ［３名（８．１％）］のどちらよりも、３０ＤＭ／３０Ｑグループで多くの被験者［２３名（３２．９％）］を悩ませた。しかしながら、３０ＤＭ／３０Ｑグループでは、悪心は、２３名の被験者のうち２０名で軽度または中程度であると判断されたが、２３名の被験者のうち１９名で３０ＤＭ／３０Ｑによる治療と少なくとも関係があるかもしれないと判断された。ＤＭグループおよびＱグループでの悪心の事例はすべて、軽度または中程度であり、１件を除くすべてが、治療と少なくとも関係があるかもしれないと判断された。めまいも、ＤＭグループ［５名（１５．２％）］またはＱグループ［１名（２．７％）］のどちらよりも、３０ＤＭ／３０Ｑグループで多くの被験者［１４名（２０％）］によって報告された。この有害事象の事例はすべて、全治療グループで、軽度または中程度であり、ほとんどすべての例が、治療と少なくとも関係があるかもしれないと判断された。傾眠は、ＤＭグループ［１名（３．０％）］またはＱグループ［０名（０％）］のどちらよりも、３０ＤＭ／３０Ｑグループで多くの被験者［９名（１２．９％）］によって報告された３番目の事象であった。この有害事象の事例はすべて、全治療グループで、軽度または中程度であり、ほとんどすべての例が、治療と少なくとも関係があるかもしれないと判断された。３名の被験者が、有害事象として下痢を経験し、その全員がＤＭグループの者であった。この事象の事例はすべて軽度であり、すべての事例が治療と関係があると判断された。

Nausea is the most common adverse event experienced in the 30DM / 30Q group, rather than in either the DM group [2 (6.1%)] or the Q group [3 (8.1%)]. Many subjects [23 (32.9%)] were bothered. However, in the 30DM / 30Q group, nausea was determined to be mild or moderate in 20 of 23 subjects, but 19 of 23 subjects were at least related to treatment with 30DM / 30Q. It was judged that there might be. All cases of nausea in the DM and Q groups were mild or moderate, and all but one were judged to be at least related to treatment. Vertigo also depends on more subjects [14 (20%)] in the 30DM / 30Q group than either the DM group [5 (15.2%)] or the Q group [1 (2.7%)]. Reported. All cases of this adverse event were mild or moderate in all treatment groups, and almost all cases were judged to be at least related to treatment. Somnolence is caused by more subjects [9 (12.9%)] in the 30DM / 30Q group than either the DM group [1 (3.0%)] or the Q group [0 (0%)]. This was the third event reported. All cases of this adverse event were mild or moderate in all treatment groups, and almost all cases were judged to be at least related to treatment. Three subjects experienced diarrhea as an adverse event, all of whom were from the DM group. All cases of this event were mild and all cases were judged to be related to treatment.

  A total of 22 subjects withdrew from the study due to adverse events. 17 (24.3%) were in the 30DM / 30Q group, 2 (6.1%) were in the DM group, and 3 were (8.1%) in the Q group. Seventeen subjects in the 30DM / 30Q group experienced 50 adverse events, most of which [17 (34%)] were related to the nervous system. These 50 events were all considered mild or moderate, with the exception of four, and all but one were judged to be at least related to treatment. One subject suffered from severe headache, one subject suffered severe nausea and severe vomiting, and one subject suffered severe respiratory failure. The subject died as a result of respiratory failure. This was judged to be unrelated to the investigational drug. The other two subjects recovered without sequelae.

  In the DM group, 7 adverse events were experienced by 2 subjects. All but one of these events were mild or moderate and all were considered to be related to treatment. One subject who experienced 6 of 7 adverse events experienced severe diarrhea, received appropriate medication for the disease, and recovered without sequelae.

  In Q group, 3 subjects experienced 5 adverse events. One subject suffered from a severe kidney infection determined to be unrelated to treatment, and one subject experienced severe muscle spasms determined to be related to treatment. Both of these subjects recovered without sequelae. All other adverse events were mild or moderate and most were judged to be unrelated to treatment.

  Overall, in this study, four severe adverse events were experienced by the subjects. Three subjects in the 30DM / 30Q group reported severe adverse events, but only one of them stopped taking the drug. All three of these serious adverse events were determined to be unrelated to the study drug. The remaining one serious adverse event was experienced by Q group subjects. The subject continued to take the study drug, and adverse events were determined to be unrelated to the study drug. There was one death in the study, and one subject in the 30DM / 30Q group died of respiratory failure unrelated to study treatment.

From baseline to day 29, there is no statistically significant change in hematology, clinical chemistry, or urinalysis values in any treatment group, and the DM group CPK is 30 DM / 30Q group There were no statistically significant changes between treatment groups in any of the laboratory values, except for a significant increase compared. From baseline to day 29, there were no clinically relevant changes in systolic blood pressure, diastolic blood pressure, heart rate, or respiration. From baseline to day 29, there were no clinically relevant changes in physical examination results. From baseline to day 29, there was a statistically significant difference in VR and QT intervals between the 30DM / 30Q group and the Q group. However, these changes were very small and were not clinically relevant. There were no statistically significant differences in QT _c , PR, and QRS duration between treatment groups.

  Since the type, frequency, and intensity of adverse events were acceptable in this target population and there were no clinically relevant findings for any other safety variable, 30DM / 30Q was It is safe.

  The CYP2D6 genotype for each treatment group in the safety population was determined and is shown in Table 36. The ITT population did not include hypometabolites as defined in the statistical analysis plan. In all treatment groups of the ITT population, high metabolizers were the most prevalent genotype.

この複合製品中のＱは、ＤＭの急速な初回通過代謝を抑制する。したがって、３０ＤＭ／３０Ｑを与えられた被験者では血漿中のＤＭ濃度がより高くなり、その代謝物であるＤＸの濃度がより低くなるはずであると予想した。３０ＤＭ／３０Ｑを与えられるグループとＤＭを与えられるグループのＤＭおよびＤＸの濃度を表３７に示す。

Q in this composite product inhibits the rapid first pass metabolism of DM. Therefore, it was expected that subjects given 30DM / 30Q would have higher plasma DM concentrations and lower concentrations of its metabolite DX. Table 37 shows the concentrations of DM and DX for the group given 30DM / 30Q and the group given DM.

平均ＤＭ濃度は、３０ＤＭ／３０ＱグループでＤＭグループの１８．６倍の高さであり、平均ＤＸ濃度は、３０ＤＭ／３０ＱグループでＤＭグループの３．３分の１の低さであった。これらの差は、両方とも統計学的に有意であった。全被験者の血漿レベルについてのデータは、調査薬物の最終服用から８時間以内に血液を採取されたこの被験者のものと同じ結果を示す。

The average DM concentration in the 30DM / 30Q group was 18.6 times as high as that of the DM group, and the average DX concentration was 3.3 times lower in the 30DM / 30Q group than that of the DM group. Both of these differences were statistically significant. Data on plasma levels for all subjects show the same results as for those subjects whose blood was collected within 8 hours of the last dose of study drug.

  The test results showed that 30DM / 30Q was statistically significantly more effective than its constituents in treating pseudobulbar affect, as demonstrated by the primary endpoint and all secondary endpoints Has been demonstrated. An expected adverse event was reported and no unexpected safety issues were raised. In the 30DM / 30Q group, more subjects had adverse events than in any other group, and 17 subjects in the 30DM / 30Q group discontinued the study due to adverse events. However, all but four adverse events in discontinued subjects were mild or moderate. Only 2 out of 17 subjects were associated with severe adverse events (headache, nausea, vomiting), which were debilitating but resolved without sequelae. Three subjects treated with 30DM / 30Q were associated with severe events, all of which were unrelated to this treatment. Furthermore, the results of evaluating QOL and QOR are significantly and statistically significantly better in subjects treated with 30DM / 30Q, so the drug benefit is greater than the discomfort caused by the adverse event It was a thing. Thus, 30DM / 30Q was very effective in treating pseudobulbar emotions in ALS subjects and the drug was safe and well tolerated.

Clinical study # 5
The primary objective of this study is to include dextromethorphan hydrobromide and quinidine sulfate during an open-label, escalation study up to the maximum tolerated dose (MTD) of subjects not exceeding DM 120 mg / Q 120 mg per day Was to evaluate the safety and tolerability of capsules (DM / Q). The second objective was to obtain a preliminary assessment of the effectiveness of DM / Q in the treatment of pain associated with diabetic neuropathy.

  This was an open-label, step-by-step study of subjects with pain associated with diabetic neuropathy. After reviewing for inclusion / non-adoption criteria, subjects were given a washout period to stop all analgesics. This was followed by 29 days of treatment with capsules containing DM 30 mg / Q 30 mg, starting with 1 capsule per day and gradually increasing to the maximum allowable amount of 4 capsules per day every week. . Subjects who cannot tolerate the dose level can return to their previous dose, take a capsule containing DM15 mg / Q30 mg instead, or discontinue the study if they cannot tolerate the minimum dose level. It was.

Within 4 weeks before the first day of taking, subjects were examined for general health including electrocardiogram measurements. The first dose of DM / Q was administered at the clinic and a resting electrocardiogram was obtained 1 hour after this dose and interpreted on the spot. If the corrected QT interval (QT _c ) determined in this preliminary interpretation is not ≧ 450 ms for men and ≧ 470 ms for women, and QT _c changes more than 30 ms from the screening ECG, Subjects were given study medication and taken as directed by the physician. Subjects were instructed about the study medication taken and the use of a daily diary to record scores from sleep, the time and average pain intensity, and an assessment scale for activity.

  Subjects visited the clinic every two weeks during the 4-week study period and were contacted by phone during the week when they did not visit the clinic. At each subsequent study visit or weekly call, subjects were presented with a pain intensity rating scale and a pain relief rating scale, and were asked about all adverse events that occurred since the last visit. Peripheral neuropathy quality of life (QOL) measurement was performed on subjects on day 1 and day 29 (or at the last visit). At day 15 and day 29 visits, blood samples were taken to determine plasma concentrations of DM, DX, and Q.

  The selected subjects were between 18 and 80 years of age (including 18 and 80 years) and were definitely diagnosed with diabetes. Subjects have <12% total glycosylated hemoglobin (HbAlc), are tolerated glycemic control, have received established diabetes treatment for at least 3 months, and have clinically distal symmetric diabetic neuropathy. He had been diagnosed with the pain associated with diabetic neuropathy for the past three months. Subjects were scored moderately or better (≧ 2) on the pain intensity rating scale before being given DM / Q on the first day.

  Every effort was made to keep each subject participating in the study. However, if the subject decided to decline, every effort was made to complete all assessments and the subject was given an explanation of why the subject declined.

  Subjects were given capsules containing DM 30 mg / Q 30 mg or DM 15 mg / Q 30 mg with increasing doses up to DM 120 mg / Q 120 mg. The study drug was given as a hard gelatin capsule, with capsule A in an opaque orange color and capsule B in an opaque white color. The contents of the capsule are listed in Table 38.

表３９に示すように、被験者に、ＤＭ／Ｑを含有するカプセルを、投与量を徐々に増やしながら与えた。用量レベルに耐えられなかった被験者は、その前のレベルに戻るか、ＤＭ１５ｍｇ／Ｑ３０ｍｇを含有するカプセルを代わりに服用するか、あるいは最低用量レベルに耐えられなかった場合、試験を中止してよいこととした。

As shown in Table 39, subjects were given capsules containing DM / Q with gradually increasing doses. Subjects who cannot tolerate the dose level may return to the previous level, take a capsule containing DM 15 mg / Q 30 mg instead, or discontinue the study if they cannot tolerate the minimum dose level It was.

被験者は、試験の間または１日目の服用開始前の１週間（または適切であれば２週間）は、禁じられた薬物を服用できないことにしていた。これらの薬物には、アマンタジン、アミトリプチリン、セントジョンズワートを含むすべての抗うつ薬、すべてのモノアミンオキシダーゼ阻害剤、鎮痛剤（アセトアミノフェンのみを使用できることとした）、カプトプリル、シメチジン、炭酸脱水素酵素阻害剤、デシプラミン、デキストロメトルファン（ＯＴＣ咳止め薬）、ジゴキシン、ジルチアゼム、エリスロマイシン、フルオキセチン、ハロペリドール、イミプラミン、イトラコナゾール、ケトコナゾール、ノルトリプチリン、パロキセチン、キニジンまたは他の抗不整脈薬、重炭酸ナトリウム、チアジド系利尿薬、およびベラパミルが含まれる。被験者が、鎮痛剤なしでウォッシュアウト期間を終了できなかった場合、他の禁じられた非鎮痛剤の十分なウォッシュアウトを行ったという条件で、その被験者にはこの試験の用量増加段階を開始することを許可した。毎日の低用量のアスピリンは鎮痛剤でないとみなし、心臓病予防のために許可した。

The subject had decided not to take the forbidden drugs during the study or for a week (or two weeks if appropriate) before the start of taking the first day. These drugs include all antidepressants including amantadine, amitriptyline, St. John's wort, all monoamine oxidase inhibitors, analgesics (assuming only acetaminophen can be used), captopril, cimetidine, carbonic acid dehydrogenase Inhibitor, desipramine, dextromethorphan (OTC cough medicine), digoxin, diltiazem, erythromycin, fluoxetine, haloperidol, imipramine, itraconazole, ketoconazole, nortriptyline, paroxetine, quinidine or other antiarrhythmic drugs, sodium bicarbonate, thiazide Drugs, and verapamil are included. If a subject fails to complete the washout period without an analgesic, the subject will begin the dose escalation phase of this study, provided that he has adequately washed out other forbidden non-analgesic agents. Allowed that. A low daily dose of aspirin was considered not an analgesic and allowed to prevent heart disease.

  Acetaminophen was the only analgesic approved as a relief analgesic and was taken at the dose indicated on the packaging label. Instruct subjects to consult with the investigator before taking any medication, including over-the-counter (OTC) medications, and also contain other analgesics (eg, codeine) or dextromethorphan Advised that products containing acetaminophen should be avoided.

  Subjects were instructed to bring unused investigational drugs to the clinic on the 15th day and return all unused investigational drugs to the clinic at the final visit. Diary cards were collected from the subjects at these visits. The total number of minutes taken was divided by the total number of prescriptions and multiplied by 100 to calculate the percent taken.

  Safety was assessed by the following measurements: adverse events, laboratory values, vital signs, physical examination, electrocardiogram, and nerve conduction velocity measurements.

  At screening and on day 29 (or at the last visit), subjects were subjected to nerve conduction testing. Nerve conduction velocity was measured by surface stimulation and recording. Bilateral sural nerve sensory tests and unilateral peroneal nerve motor tests were performed or managed by a clinical electromyograph certified by the American Board of Electrodiagnostic Medicine. Standardized techniques to minimize variability between electromyographs. In all tests, the limb temperature was kept above the standard temperature. The results were interpreted by the Central Decoding Laboratory.

  Efficacy depends on the following measures: pain intensity rating scale, current pain intensity scale by diary, pain reduction rating scale, activity rating scale by diary, peripheral neuropathy QOL measurement, average pain rating scale by diary, and diary It was evaluated by the sleep rating scale.

  Pain intensity rating scores were determined on days 8, 15, 22, and 29 (or at the last visit). The subject used a five-point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme) to determine the amount of pain experienced in the lower limb within the previous 24 hours. Indicated. Subjects were asked to complete a pain intensity rating scale at the clinic on the 15th and 29th days (or at the last visit) before entering the first day study. This scale was also performed verbally by calling the subject during the week when the visit was not scheduled (Days 8 and 22).

  The pain relief rating scale was entered on days 8, 15, 22, and 29 (or at the last visit). Subjects used a 6-step Likert scale (-1 = worse, 0 = none, 1 = somewhat 2 = moderate, 3 = highly 4 = complete) and the end of the washout / screening period In comparison, the amount of pain relieved in the lower limbs was shown. Subjects were asked to complete this scale at the clinic on days 15 and 29 (or at the last visit). Pain relief rating scales were also made verbally by calling the subjects during the weeks when the visit was not scheduled (Days 8 and 22).

  QOL scores were obtained at the clinic on days 1 and 29 (or at the last visit). QOL is described in Vickrey et al., Neurorehab. Neurol. Evaluation was performed using a Peripheral Neuropathy QOL Instrument-97 as described in Repair, 2000, Vol. 14, pp. 93-104. This is a self-measuring, health-related QOL measurement for peripheral neuropathy. This includes additional questions that have been fully incorporated into the Health Status Survey SF-36 scale and have been determined to be particularly relevant to subjects with peripheral neuropathy.

  This measure includes items for general health issues, detailed peripheral neuropathy issues, health symptoms or problems, general health assessments, and general and health conditions 21 Includes subscales. Except for disability days, overall health assessment (0-100), and yes / no questions about sexual activity, all items use a 3, 4, 5, or 6-level sectoral rating scale. ing.

  To analyze the QOL results, a scoring algorithm was used to convert the departmental item ratings into the appropriate percent ratings. The most favorable evaluation value is 100%, the most unfavorable evaluation value is 0%, and the intermediate percentages are equally spaced according to the number of scale steps (for example, 0, 25, 50, 75 for the five-level ascending scale) , 100; 100, 50, 0 on a three-step descending scale). The converted evaluation values for each item of the lower scale were averaged to obtain the score of the lower scale. All subscale scores were constructed to reflect results that favored higher values. A composite QOL score was obtained by averaging all subscale scores excluding days of disability.

  The subject's diary included a sleep rating scale and current pain intensity scale to be written in the morning, and an activity rating scale and an average pain rating scale to be written in the evening. On the sleep rating scale, a scale of 0 to 10 that best describes the extent to which the subject has disturbed his / her sleep in the last 24 hours (0 = not disturb, 10 = completely disturbed). Instructed to enclose the numbers. The Current Pain Intensity Scale gives the subject the best description of their current pain intensity: 0-no pain, 1-mild, 2-unpleasant, 3-pain. He was instructed to surround 4-severe and 5-unbearable. On the activity rating scale, subjects rated 0 to 10 (same as the sleep rating scale) that best describes the extent to which pain has interfered with their general activity over the past 24 hours (same as sleep rating scale) (0 = disturbed) It was instructed to enclose the numbers (10 = completely hindered). On the average pain rating scale for the past 12 hours, subjects are assigned a scale of 0-10 (same as the sleep rating scale) that best describes their average pain intensity for the past 12 hours (0 = none, (10 = the worst pain so far) was instructed to surround. The rating scale used as a measure of effectiveness is a well-established tool in pain studies, and in particular, the peripheral neuropathy QOL measurement method contains subject-specific material for peripheral neuropathy.

  The efficacy assessment consisted of speculative analysis and summary statistics and was calculated for the following variables for all subjects and subjects classified by MTD (except where annotated). That is, changes from baseline in the pain intensity rating scale on Days 8, 15, 22, and 29 (or at the last visit); Day 8, Day 15, Day 22, and Pain relief rating scale score on day 29 (or at the last visit); change from baseline in peripheral neuropathy quality of life measurement composite score on day 29 (or at the last visit); sleep assessment in diary Sleep disturbance score calculated from the values recorded for the scale (the score on day 15 is the average of the sleep rating scale scores from the diaries of subjects on days 13, 14, and 15; day 29 Score is the average of the 27, 28, and 29 scores; the score at the last visit is the average of the last 3 consecutive days of study treatment); recorded in the subject's diary The current daily Pain intensity, activity, pain, and sleep rating scale;% of subjects score for each efficacy variable was improved.

  The properties of the subject are shown in FIG. In this figure, and in each subsequent tabulation table and each figure, subjects are classified by the MTD group. The indicated MTDs were administered to subjects in the 30 mg, 60 mg, and 90 mg groups, with the exception of subjects with MTD of 45 mg (see below), classified in the 60 mg group. Subjects in the 120 mg group tolerated this dose, which is the highest dose allowed in this study, but not strictly MTD. For the sake of brevity, these groupings are all called “MTD”.

  Of the 36 subjects who participated and received study medication, 33 completed the study. One subject completed the study with DM45 mg MTD. Since there was only one subject with this MTD, this subject is included together in the 60 mg MTD group in the data table and FIG. The number of subjects in each MTD group and all test sites is reported in Table 40.

データ分析では１集団のみを使用した。分析および集計は、調査薬物を服用した３６名の被験者全員を使用して行った。調査集団の個体群統計学的特徴を表４１で報告する。

Only one population was used for data analysis. Analysis and tabulation were performed using all 36 subjects who took the study drug. The demographic characteristics of the study population are reported in Table 41.

被験者の糖尿病性ニューロパシーの病歴を表４２にまとめて示す。

The history of diabetic neuropathy of the subjects is summarized in Table 42.

この試験に参加した被験者は、以前から最低で０．２年間、最高で２４．３年間（中央値が２．５年間）、糖尿病性ニューロパシーの診断を受けていた。被験者は、最低で４カ月間、最高で１８０カ月間／１５．０年間（中央値が２４．０カ月間／２．０年間）、糖尿病性ニューロパシーからくる痛みを毎日経験していた。

Subjects who participated in this study had previously been diagnosed with diabetic neuropathy for a minimum of 0.2 years and a maximum of 24.3 years (median 2.5 years). Subjects experienced daily pain from diabetic neuropathy for a minimum of 4 months and a maximum of 180 months / 15.0 years (median 24.0 months / 2.0 years).

  Concurrent drugs were reported for 30 days prior to the study and during the treatment period. Concomitant medications reported by at least 10% of all subjects are listed in Table 43 in WHO terminology.

救済薬（アセトアミノフェン）の使用は限られていた。４名の被験者だけが救済薬を服用した。すなわち、１名は、２９日の試験日のうち２８日アセトアミノフェンを服用し、もう１名は１６試験日服用し、２名が１試験日だけ服用した。全体として、この試験の間、痛みのために救済薬を使用することはほとんどなく、被験者は、それぞれ、平均１．３日（試験日数の４．５％）救済薬を服用した。

The use of rescue medication (acetaminophen) was limited. Only four subjects took relief medication. That is, one person took acetaminophen on the 28th of the 29th test day, the other took 16 test days, and 2 took only one test day. Overall, there was very little use of salvage medications for pain during this study, and each subject took an average of 1.3 days (4.5% of study days).

  Table 44 shows the degree of exposure to the investigational drug.

有害事象を伴った被験者の数を表４５で報告する。

The number of subjects with adverse events is reported in Table 45.

被験者の大多数が、試験の間に少なくとも１件の有害事象を経験した。ほぼすべての有害事象は、強度が軽度または中程度であった。４名の被験者が、合計７件の重度の有害事象を経験した。２名の被験者が、４件の重度の有害事象を経験した。１名の被験者は、重度の不眠症を患い、調査薬物の用量を減らすと回復し；１名の被験者は、重度の疲労および重度の悪寒を患い、調査薬物の変更なしで回復した。全部で少なくとも５％の被験者が経験した有害事象を表４６で報告する。

The majority of subjects experienced at least one adverse event during the study. Almost all adverse events were mild or moderate in intensity. Four subjects experienced a total of 7 serious adverse events. Two subjects experienced 4 severe adverse events. One subject suffered severe insomnia and recovered when the study drug dose was reduced; one subject suffered severe fatigue and severe chills and recovered without changes in the study drug. Adverse events experienced by at least 5% of all subjects are reported in Table 46.

悪心は、経験された最も一般的な有害事象であり、全体で１０名（２７．８％）の被験者で起こった。悪心は、７名の被験者（１９．４％）で軽度であると判断され、３名の被験者で中程度であると判断された。すべての場合で、悪心は、治療と少なくとも関係があるかもしれないと判断された。最大耐量と、悪心の発生率、重症度、または調査薬物との関係との間に明らかな関連性はなかった。めまいは、全体で９名の被験者（２５．０％）によって報告された。めまいは、６名の被験者（１６．７％）で軽度、３名の被験者（８．３％）で中程度であった。これらの被験者の大多数（７対２）について、めまいは、治療と少なくとも関係があるかもしれないと判断された。９名の被験者（２５．０％）が頭痛を報告した。この有害事象の事例はすべて、軽度または中程度であり、大多数（９例中６例）が治療と関係があるかもしれないと判断された。２名の被験者は、有害事象のために試験を辞退した。ＭＴＤが３０ｍｇであった１名の被験者は、切除する必要のある結腸ポリープが以前から存在していたために、調査薬物を１回服用した後に辞退した。ＭＴＤが６０ｍｇであった他方の被験者は、繰り返し発生する断続的な胸の痛みのために６日目に辞退した。

Nausea is the most common adverse event experienced and occurred in a total of 10 (27.8%) subjects. Nausea was judged to be mild in 7 subjects (19.4%) and moderate in 3 subjects. In all cases, nausea was determined to be at least related to treatment. There was no clear association between maximum tolerated dose and the incidence of nausea, severity, or relationship to study drug. Vertigo was reported by a total of 9 subjects (25.0%). Vertigo was mild in 6 subjects (16.7%) and moderate in 3 subjects (8.3%). For the majority of these subjects (7 vs. 2), it was determined that vertigo may be at least related to treatment. Nine subjects (25.0%) reported headaches. All cases of this adverse event were mild or moderate, and it was determined that the majority (6 of 9) may be related to treatment. Two subjects declined the study due to adverse events. One subject with an MTD of 30 mg declined after taking the study drug once because colon polyps needed to be excised. The other subject with an MTD of 60 mg declined on day 6 due to recurrent intermittent chest pain.

  One subject was admitted to the hospital on the day of the 29th visit, when chronic obstructive pulmonary disease (COPD) worsened and was advised to contact his physician. On day 33, the subject died suddenly while still in the hospital. The subject's physician pointed out myocardial infarction and arrhythmia as possible causes of death. The investigator noted that the COPD exacerbation of this subject was not related to the study drug, and that the male myocardial infarction and arrhythmia were unlikely to be related to the study drug.

  One subject with an MTD of 60 mg had a history of hypertension (4 years) and atypical chest pain (2 years). The woman developed intermittent chest pain that recurs on day 6 and was hospitalized on day 7. The woman discontinued study medication. All heart tests were negative. The subject recovered on the 8th day, discharged on the 9th day, and returned to work on the 10th day. The underlying cause of the subject's chest pain was unclear, and the woman's chest pain may have been related to the study drug.

  All laboratory adverse events were mild or moderate in intensity. Two subjects had increased creatine kinase levels, the other two had elevated liver enzyme levels with other abnormalities, and one subject had bloody stool. Two subjects recovered from all of their laboratory adverse events, one subject did not recover, and two subjects did not return to the study clinic for follow-up, so The result was unknown. The majority of these adverse events were judged to be “possibly” related to the investigational drug. None of the clinical laboratory adverse events were severe adverse events, and none required study drug dose reduction or discontinuation.

There were no clinically relevant changes in systolic blood pressure, diastolic blood pressure, heart rate, or respiration from baseline to day 29 for any MTD. There were no clinically relevant changes in physical examination results during the study treatment. There were no clinically relevant differences in mean QT, QT _c , PR, or QRS duration between MTD groups, or any change in ECG values during the study.

  At screening, there was no significant difference in motor conduction velocity in the distal radial nerve section between the radial head and ankle for each of the four stage MTD groups. The average baseline motion conduction velocity was 39.2 m / sec (range 26.6-49.0 m / sec). There was also no difference between the changes in motor nerve conduction from screening to the last visit for each MTD group. The average change in motion conduction velocity in the rib head-ankle segment for the entire study population was 0.8 m / sec (range of -4.0 to +7.7 m / sec). In the 120 mg MTD group (−6.7 m / sec) and the entire study population (−5.5 m / sec), there was a marked decrease in conduction velocity in the proximal radial nerve section between the radial head and popliteal fossa. However, this can be explained by the unusually high nerve conduction velocity (average 47.6 m / sec in the 120 mg MTD group, range of 21.7-66.7 m / sec) measured during the screening at the time of screening. Twelve of the 23 subjects in this group had baseline motor conduction velocities faster than 50 m / s, and these abnormally high values in this population indicate that the distance that nerves in this segment are stimulated is short. This reflected the possibility of a measurement error.

  A significant decrease in nerve conduction velocity should appear more severe in the distal nerve section, as the frequency of this condition increases with the length of the nerve pathway, as seen electrophysiologically in diabetic neuropathy. is there. For these reasons, the proximal conduction velocity measured in this study was not interpreted as a measure of the safety or tolerability of the study drug, but as an assessment of the presence of local radial neuropathy in the radial head. In conclusion, there was no electrophysiological evidence that the analgesic properties of DM / Q were due to toxic effects on peripheral nerves.

  The DM / Q combination with a daily dose of DM 30 mg / Q 30 mg to DM 120 mg / Q 120 mg was safe and well tolerated in this subject population. The type, frequency, and intensity of adverse events were within acceptable limits. Five subjects had at least one clinical laboratory adverse event, all of mild or moderate intensity, none of which needed to change study medication use. No clinical concerns were found regarding vital signs, physical examination, or electrocardiogram results. No clinically significant changes in nerve conduction velocity were detected. The study treatment was well tolerated and the majority of subjects had the highest tolerated MTD (DM120 mg / Q120 mg).

  The frequency of subjects for each pain intensity score at each time point is reported in Table 47.

１日目（ベースライン）では、プロトコルの採用基準で指定したように、全被験者の疼痛強度が２（中程度）以上であった。最終来診までに、少数の被験者（２０．０％）だけが中程度以上の痛みを伴い、４０％は痛みを報告しなかった。

On day 1 (baseline), as specified in the protocol adoption criteria, all subjects had a pain intensity of 2 (medium) or higher. By the final visit, only a small number of subjects (20.0%) had moderate or higher pain and 40% reported no pain.

  The change from baseline in the pain intensity rating scale score is reported in Table 48.

疼痛強度評価尺度の平均スコアは、被験者全体で、ベースラインとその後の各来診時の間に減少した。この減少は大いに有意であった（ｐ値はすべて＜０．０００１）。ベースラインから最終来診時にかけての変化については、スコアの減少がＭＴＤと有意に関係していたが（ｐ＝０．０３４８）、他のどの来診時についても、スコアに対するＭＴＤの有意な影響がなかった（ｐ値はすべて≧０．１６２８）。

The average score on the pain intensity scale decreased across subjects between the baseline and each subsequent visit. This reduction was highly significant (all p values <0.0001). For changes from baseline to the last visit, a decrease in score was significantly associated with MTD (p = 0.0348), but for any other visit, the significant effect of MTD on the score (P values are all ≧ 0.1628).

  The frequency of subjects with each pain relief score at each study visit is reported in Table 49.

一般に、試験の間、疼痛軽減スコアは増加した。８日目では、「大いに」または「完全に」痛みが軽減したと報告した被験者は３３．３％だけであったが；最終来診時までには、大多数（６４．７％）がそのように報告した。どの来診時でも、ベースラインに比べて「より悪い」痛みを報告した被験者はなく、１名の被験者だけが、８日目の後のいずれの来診時にも「なし」と報告した。

In general, pain relief scores increased during the study. On day 8, only 33.3% of subjects reported “very much” or “completely” pain relief; by the time of the final visit, the majority (64.7%) As reported. None of the subjects reported “worse” pain compared to baseline at any visit, and only one subject reported “none” at any visit after Day 8.

  Summary statistics of pain relief scale scores are reported in Table 50.

疼痛軽減評価尺度の平均スコアは、被験者全体で、８日目の最初の評価からその後の各来診時まで有意に増加した（ｐ値はすべて＜０．０００１）。いずれの来診時でも、疼痛軽減スコアに対するＭＴＤの有意な影響はなかった（ｐ値はすべて≧０．４８８０）。

The average score on the pain relief rating scale was significantly increased across all subjects from the first assessment on day 8 to each subsequent visit (all p-values were <0.0001). There was no significant effect of MTD on pain relief scores at any visit (all p-values ≧ 0.4880).

  The changes from baseline in the composite score from the peripheral neuropathy QOL measurement are reported in Table 51.

末梢神経障害ＱＯＬ測定法の平均複合スコアは、被験者全体で、１日目（ベースライン）から２９日目にかけて、および最終来診時にかけて有意に増加した（すなわち、向上した）（ｐ値は共に＜０．０００１）。ベースラインから２９日目または最終来診時にかけての変化は、ＭＴＤと関係がなかった（ｐ値はすべて≧０．１８３７）。

Peripheral neuropathy QOL measurement mean composite scores increased significantly (ie improved) from day 1 (baseline) to day 29 and at the last visit across subjects (both p-values) <0.0001). Changes from baseline to day 29 or at the last visit were not related to MTD (all p values> 0.1837).

  The p-value for the change in individual QOL scale from baseline to the last visit is reported in Table 52.

個々のＱＯＬ尺度項目の大多数は、ベースラインと最終来診時の間に有意に向上した（１５／２１，７４．１％）。

The majority of individual QOL scale items improved significantly between baseline and the last visit (15/21, 74.1%).

  The sleep disturbance scores calculated for day 15, day 29, and at the last visit are reported in Table 53.

平均睡眠妨害スコアは試験中に低下し、被験者の痛みによる睡眠の妨害が減少したことが示された。いずれの来診時でも、睡眠妨害スコアに対するＭＴＤの有意な影響はなかった（ｐ値はすべて≧０．１０７７）。睡眠評価尺度から得られた結果は、図４に試験日を横軸にとって表す。睡眠スコアは、２日目から最終試験日にかけて有意に減少した（回帰ｐ＜０．００１）（スコアが低いほど、睡眠の妨げになると判断される痛みが少ない）。

The average sleep disturbance score decreased during the study, indicating that subject's pain caused sleep disturbance. There was no significant effect of MTD on sleep disturbance scores at any visit (all p values ≧ 0.1077). The results obtained from the sleep rating scale are represented on the horizontal axis in FIG. The sleep score decreased significantly from the second day to the last test day (regression p <0.001) (the lower the score, the less pain that is judged to interfere with sleep).

  The results obtained from the current pain intensity rating scale are represented on the horizontal axis in FIG. The current pain intensity score decreased significantly from the second day to the last test day (regression p <0.001). The results obtained from the activity evaluation scale are represented on the horizontal axis in FIG. The activity score decreased significantly from day 1 to the last test day (regression p <0.001) (the lower the score, the less pain that is judged to interfere with general activity). The results obtained from the pain rating scale are represented on the horizontal axis in FIG. The average pain score for the previous 12 hours decreased significantly from day 1 to the last study day (regression p <0.001).

  An improvement in efficacy score was defined as an improvement from the first recorded value to the last recorded value, with the exception of the pain relief rating scale which defined the last recorded value as a value> 0. The frequency of subjects whose scores improved during the study is shown in Table 54 for each efficacy measure.

どの有効性の測定値でも、有意な割合の被験者が試験中に向上を示した（ｐ値はすべて≦０．０３９６）。向上は、有効性の測定値のいずれについても、ＭＴＤと関係がなかった（ｐ値はすべて≧０．１６６８）。

At any efficacy measure, a significant proportion of subjects showed improvement during the study (all p-values were ≦ 0.0396). Improvement was not related to MTD for any of the efficacy measures (all p-values ≧ 0.1668).

  Subjects who were open-labeled with DM / Q in the dose range of DM 30 mg / Q 30 mg to DM 120 mg / Q 120 mg experienced pain from diabetic peripheral neuropathy and the extent to which this pain hindered general activity and sleep A statistically significant reduction was reported. Subjects who received this treatment also experienced a statistically significant improvement in QOL.

  Table 55 summarizes the CYP2D6 phenotype based on the genotype results of the subjects. There were no intermediate or ultrarapid metabolizers in this study population.

１名を除くすべての被験者が高代謝者であった。９０ｍｇおよび１２０ｍｇＭＴＤグループでは、血漿中のＤＭ濃度が１５日目の来診時と最終来診時の間に増大した。代謝物ＤＸおよびＱについても、同様の濃度の増大が見られた。最終来診時の高代謝者の血漿中のＤＭ、ＤＸ、およびＱの濃度をＭＴＤごとに表５６にまとめて示す。

All but one subject were highly metabolized. In the 90 mg and 120 mg MTD groups, plasma DM levels increased between the 15th visit and the last visit. Similar increases in concentrations were seen for metabolites DX and Q. The concentrations of DM, DX, and Q in the plasma of highly metabolized people at the final visit are summarized in Table 56 for each MTD.

比較のために、低代謝者（ＭＴＤは６０ｍｇ）の最終来診時の血漿中の濃度は、ＤＭが１２６．４ｎｇ／ｍＬ、ＤＸが４１．０ｎｇ／ｍＬ、Ｑが１６５．０ｎｇ／ｍＬであった。１５日目、２９日目、および最終来診時の血漿中のＤＭ濃度と疼痛強度評価との相関を表５７にまとめて示す（高代謝者のみ）。

For comparison, plasma concentrations at the final visit of low-metabolites (MTD 60 mg) were DM of 126.4 ng / mL, DX of 41.0 ng / mL, and Q of 165.0 ng / mL. It was. Table 57 summarizes the correlation between the DM concentration in plasma and the pain intensity assessment on the 15th, 29th, and final visits (highly metabolized only).

１５日目には、血漿中のＤＭ濃度と疼痛強度評価との間に弱い負の相関があり（係数は−０．３５７２）、他の時点では、ごく僅かな相関しかなかった（≦−０．１４８７）。１５日目の相関は統計学的に有意であったが（ｐ＝０．０４７３）、２９日目および最終来診時の相関はそうでなかった（ｐ≧０．４０８８）。しかしながら、血漿中の薬物濃度と疼痛評価との間の相関が弱い、または存在しないことは、鎮痛剤の薬物動態検査の典型的な結果である。

On day 15, there was a weak negative correlation between plasma DM concentration and pain intensity assessment (coefficient -0.3572), and at other time points there was only a slight correlation (≤-0 . 1487). The correlation at day 15 was statistically significant (p = 0.0473), but not at day 29 and at the last visit (p ≧ 0.4088). However, a weak or absent correlation between plasma drug concentration and pain assessment is a typical result of analgesic pharmacokinetic studies.

  Safety results show that in the treatment of subjects with pain associated with diabetic peripheral neuropathy, the combined use of DM / Q in the dose range of DM 30 mg / Q 30 mg to DM 120 mg / Q 120 mg is safe and well tolerated. It has been proven and has shown effectiveness in reducing pain.

  Preferred embodiments have been described along with their specific embodiments. Further modifications are possible, and this application applies to the essential features described above, generally in accordance with the essence of the invention and within the known convention or practice of the industry to which the invention belongs. It is understood that any variation, use, or adaptation of the present invention is encompassed, including deviations from this disclosure as falling within the scope of the invention and any equivalents thereof. I want. All references cited herein, including but not limited to technical literature references and patents, are hereby incorporated herein by reference in their entirety.

Claims (52)

  A method of treating pseudobulbar affect or emotional instability comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is from about 20 mg / day to about A method wherein the dose is 200 mg / day and the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.   The method according to claim 1, wherein the pseudobulbaric emotion or instability is caused by a neurodegenerative disease or neurodegenerative disease, or brain injury.   A method of treating neuropathic pain comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is from about 20 mg / day to about 200 mg / day The method wherein the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.   A method of treating a neurodegenerative disease or neurodegenerative disease comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is from about 20 mg / day to about 200 mg / day. A method wherein the amount of quinidine administered is from about 10 mg / day to less than about 50 mg / day.   5. The method of claim 4, wherein the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.   A method of treating brain injury comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein the amount of dextromethorphan administered is from about 20 mg / day to about 200 mg / day, The method wherein the amount of quinidine is from about 10 mg / day to less than about 50 mg / day.   7. The method of claim 6, wherein the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event (ischemic event), hypoxic event, and neuronal cell death.   8. The method according to any one of claims 1 to 7, wherein dextromethorphan and quinidine are administered as a combined drug once a day.   8. The method according to any one of claims 1 to 7, wherein dextromethorphan and quinidine are administered as a combined drug at least twice per day.   8. The method of any one of claims 1-7, wherein the amount of quinidine administered is from about 20 mg / day to about 45 mg / day.   8. The method of any one of claims 1-7, wherein the amount of dextromethorphan administered is from about 20 mg / day to about 60 mg / day.   The method according to any one of claims 1 to 7, wherein at least one of the quinidine and the dextromethorphan is in the form of a pharmaceutically acceptable salt.   Said pharmaceutically acceptable salt is an alkali metal salt, ie lithium salt, sodium salt, potassium salt, alkaline earth metal salt ie calcium salt, magnesium salt, lysine salt, N, N′-dibenzylethylenediamine salt, Consists of chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, hydrochloride, and hydrobromide The method of claim 12, wherein the method is selected from the group.   The quinidine includes quinidine sulfate, the dextromethorphan includes dextromethorphan hydrobromide, and the amount of quinidine sulfate to be administered is about 30 mg / day to 60 mg / day, and dextromethorphan hydrobromide to be administered 13. The method of claim 12, wherein the amount is from about 30 mg / day to about 60 mg / day.   A method of treating pseudobulbar affect or emotional instability comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are administered in the form of a combination drug, The method wherein the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 1.25 or less.   16. The method of claim 15, wherein the pseudobulbaric emotion or instability is caused by a neurodegenerative disease or neurodegenerative disease, or brain injury.   A method of treating neuropathic pain comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are administered in the form of a combination drug, A method wherein the weight ratio of dextromethorphan and quinidine is about 1: 1.25 or less.   A method of treating a neurodegenerative disease or neurodegenerative disease comprising administering dextromethorphan in combination with quinidine to a patient in need thereof, wherein dextromethorphan and quinidine are administered in the form of a combination drug A method in which the weight ratio of dextromethorphan and quinidine in the drug is about 1: 1.25 or less.   19. The method of claim 18, wherein the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.   A method of treating brain injury comprising administering to a patient in need thereof dextromethorphan in combination with quinidine, wherein dextromethorphan and quinidine are administered in the form of a combination drug, A method wherein the weight ratio of tolphan and quinidine is about 1: 1.25 or less.   21. The method of claim 20, wherein the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event, hypoxic event, and neuronal cell death.   23. The method of any one of claims 15-21, wherein the weight ratio of dextromethorphan and quinidine in the combined drug is about 1: 0.75 or less.   22. The amount of quinidine administered is from about 20 mg / day to about 45 mg / day, and the amount of dextromethorphan administered is from about 20 mg / day to about 60 mg / day. the method of.   The method according to any one of claims 15 to 21, wherein at least one of the quinidine and the dextromethorphan is in the form of a pharmaceutically acceptable salt.   Said pharmaceutically acceptable salt is an alkali metal salt, ie lithium salt, sodium salt, potassium salt, alkaline earth metal salt ie calcium salt, magnesium salt, lysine salt, N, N′-dibenzylethylenediamine salt, Consists of chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, hydrochloride, and hydrobromide 25. The method of claim 24, selected from the group.   The quinidine includes quinidine sulfate, the dextromethorphan includes dextromethorphan hydrobromide, and the amount of quinidine sulfate to be administered is about 30 mg / day to about 60 mg / day, and dextrome hydrobromide to be administered 25. The method of claim 24, wherein the amount of tolphan is from about 30 mg / day to about 60 mg / day.   The method according to any one of claims 15 to 21, wherein the combined drug is administered once a day.   The method according to any one of claims 15 to 21, wherein the combined drug is administered twice or more per day.   A pharmaceutical composition suitable for use in the treatment of pseudobulbar affect or emotional instability, comprising a tablet or capsule, said tablet or capsule comprising dextromethorphan and quinidine, comprising dextromethorphan and quinidine A composition having a weight ratio of about 1: 1.25 or less.   30. The composition of claim 29, wherein the pseudobulbar affect or emotional instability is caused by a neurodegenerative or neurodegenerative disease, or brain injury.   A pharmaceutical composition suitable for use in the treatment of neuropathic pain, comprising a tablet or capsule, said tablet or capsule comprising dextromethorphan and quinidine, wherein the weight ratio of dextromethorphan and quinidine is about 1 : The composition which is 1.25 or less.   A neurodegenerative disease or a pharmaceutical composition suitable for use in the treatment of a neurodegenerative disease, comprising a tablet or capsule, wherein the tablet or capsule comprises dextromethorphan and quinidine, wherein the weight ratio of dextromethorphan and quinidine Wherein the ratio is about 1: 1.25 or less.   33. The composition of claim 32, wherein the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.   A pharmaceutical composition suitable for use in brain injury comprising a tablet or capsule, said tablet or capsule comprising dextromethorphan and quinidine, wherein the weight ratio of dextromethorphan and quinidine is about 1: 1.25. A composition that is:   35. The composition of claim 34, wherein the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event, hypoxic event, and neuronal cell death.   36. The composition of any one of claims 29 to 35, wherein the weight ratio of dextromethorphan and quinidine is about 1: 0.75 or less.   36. The composition of any one of claims 29 to 35, wherein the quinidine is present in an amount from about 20 mg to about 45 mg and the dextromethorphan is present in an amount from about 20 mg to about 60 mg.   36. The composition according to any one of claims 29 to 35, wherein at least one of the quinidine and the dextromethorphan is in the form of a pharmaceutically acceptable salt.   Said pharmaceutically acceptable salt is an alkali metal salt, ie lithium salt, sodium salt, potassium salt, alkaline earth metal salt ie calcium salt, magnesium salt, lysine salt, N, N′-dibenzylethylenediamine salt, Consists of chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, hydrochloride, and hydrobromide 40. The composition of claim 38, selected from the group.   The quinidine includes quinidine sulfate, the dextromethorphan includes dextromethorphan hydrobromide, the quinidine sulfate is present in an amount of about 30 mg to about 60 mg, and the dextromethorphan hydrobromide is about 30 mg to 40. The composition of claim 38, present in an amount of about 60 mg.   Use of dextromethorphan and quinidine in the preparation of a medicament for treating pseudobulbar affect or emotional instability, said medicament comprising a capsule or tablet, wherein dextromethorphan and quinidine are said capsule or Use present in the tablet in a weight ratio of dextromethorphan and quinidine of 1: 1.25 or less.   42. Use according to claim 41, wherein the pseudobulbaric emotion or emotional instability is caused by a neurodegenerative or neurodegenerative disease, or brain injury.   Use of dextromethorphan and quinidine in the preparation of a medicament for treating neuropathic pain, said medicament comprising a capsule or tablet, wherein dextromethorphan and quinidine are in the capsule or tablet 1 : Use present in a weight ratio of dextromethorphan and quinidine of 1.25 or less.   Use of dextromethorphan and quinidine in the preparation of a neurodegenerative disease or a medicament for treating a neurodegenerative disease, said medicament comprising a capsule or tablet, wherein dextromethorphan and quinidine are in said capsule or tablet Use at a weight ratio of dextromethorphan and quinidine of 1: 1.25 or less.   45. Use according to claim 44, wherein the neurodegenerative disease or neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease.   Use of dextromethorphan and quinidine in the preparation of a medicament for treating brain injury, said medicament comprising a capsule or tablet, wherein dextromethorphan and quinidine are 1: 1 in said capsule or tablet. Uses present in a dextromethorphan to quinidine weight ratio of 25 or less.   47. The use of claim 46, wherein the brain injury is selected from the group consisting of stroke, traumatic brain injury, ischemic event, hypoxic event, and neuronal cell death.   48. Use according to any one of claims 41 to 47, wherein dextromethorphan and quinidine are present in the capsule or tablet in a weight ratio of dextromethorphan and quinidine of 1: 0.75 or less.   48. Use according to any one of claims 41 to 47, wherein at least one of the quinidine and the dextromethorphan is in the form of a pharmaceutically acceptable salt.   Said pharmaceutically acceptable salt is an alkali metal salt, ie lithium salt, sodium salt, potassium salt, alkaline earth metal salt ie calcium salt, magnesium salt, lysine salt, N, N′-dibenzylethylenediamine salt, Consists of chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, meglumine salt, procaine salt, tris salt, free acid salt, free base salt, inorganic salt, ie sulfate, hydrochloride, and hydrobromide 50. Use according to claim 49, selected from the group.   The quinidine includes quinidine sulfate, the dextromethorphan includes dextromethorphan hydrobromide, the quinidine sulfate is present in an amount of about 30 mg to about 60 mg, and the dextromethorphan hydrobromide is about 30 mg to 50. Use according to claim 49, present in an amount of about 60 mg.   48. The use according to any one of claims 41 to 47, wherein the quinidine is present in an amount of about 20 mg to about 45 mg and the dextromethorphan is present in an amount of about 20 mg to about 60 mg.

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